Project acronym A-HERO
Project Anthelmintic Research and Optimization
Researcher (PI) Jennifer Irene Keiser
Host Institution (HI) SCHWEIZERISCHES TROPEN- UND PUBLIC HEALTH-INSTITUT
Call Details Consolidator Grant (CoG), LS7, ERC-2013-CoG
Summary "I propose an ambitious, yet feasible 5-year research project that will fill an important gap in global health. Specifically, I will develop and validate novel approaches for anthelmintic drug discovery and development. My proposal pursues the following five research questions: (i) Is a chip calorimeter suitable for high-throughput screening in anthelmintic drug discovery? (ii) Is combination chemotherapy safe and more efficacious than monotherapy against strongyloidiasis and trichuriasis? (iii) What are the key pharmacokinetic parameters of praziquantel in preschool-aged children and school-aged children infected with Schistosoma mansoni and S. haematobium using a novel and validated technology based on dried blood spotting? (iv) What are the metabolic consequences and clearance of praziquantel treatment in S. mansoni-infected mice and S. mansoni- and S. haematobium-infected children? (v) Which is the ideal compartment to study pharmacokinetic parameters for intestinal nematode infections and does age, nutrition, co-infection and infection intensity influence the efficacy of anthelmintic drugs?
My proposed research is of considerable public health relevance since it will ultimately result in improved treatments for soil-transmitted helminthiasis and pediatric schistosomiasis. Additionally, at the end of this project, I have generated comprehensive information on drug disposition of anthelmintics. A comprehensive database of metabolite profiles following praziquantel treatment will be available. Finally, the proof-of-concept of chip calorimetry in anthelmintic drug discovery has been established and broadly validated."
Summary
"I propose an ambitious, yet feasible 5-year research project that will fill an important gap in global health. Specifically, I will develop and validate novel approaches for anthelmintic drug discovery and development. My proposal pursues the following five research questions: (i) Is a chip calorimeter suitable for high-throughput screening in anthelmintic drug discovery? (ii) Is combination chemotherapy safe and more efficacious than monotherapy against strongyloidiasis and trichuriasis? (iii) What are the key pharmacokinetic parameters of praziquantel in preschool-aged children and school-aged children infected with Schistosoma mansoni and S. haematobium using a novel and validated technology based on dried blood spotting? (iv) What are the metabolic consequences and clearance of praziquantel treatment in S. mansoni-infected mice and S. mansoni- and S. haematobium-infected children? (v) Which is the ideal compartment to study pharmacokinetic parameters for intestinal nematode infections and does age, nutrition, co-infection and infection intensity influence the efficacy of anthelmintic drugs?
My proposed research is of considerable public health relevance since it will ultimately result in improved treatments for soil-transmitted helminthiasis and pediatric schistosomiasis. Additionally, at the end of this project, I have generated comprehensive information on drug disposition of anthelmintics. A comprehensive database of metabolite profiles following praziquantel treatment will be available. Finally, the proof-of-concept of chip calorimetry in anthelmintic drug discovery has been established and broadly validated."
Max ERC Funding
1 927 350 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym Antibodyomics
Project Vaccine profiling and immunodiagnostic discovery by high-throughput antibody repertoire analysis
Researcher (PI) Sai Tota Reddy
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Vaccines and immunodiagnostics have been vital for public health and medicine, however a quantitative molecular understanding of vaccine-induced antibody responses is lacking. Antibody research is currently going through a big-data driven revolution, largely due to progress in next-generation sequencing (NGS) and bioinformatic analysis of antibody repertoires. A main advantage of high-throughput antibody repertoire analysis is that it provides a wealth of quantitative information not possible with other classical methods of antibody analysis (i.e., serum titers); this information includes: clonal distribution and diversity, somatic hypermutation patterns, and lineage tracing. In preliminary work my group has established standardized methods for antibody repertoire NGS, including an experimental-bioinformatic pipeline for error and bias correction that enables highly accurate repertoire sequencing and analysis. The overall goal of this proposal will be to apply high-throughput antibody repertoire analysis for quantitative vaccine profiling and discovery of next-generation immunodiagnostics. Using mouse subunit vaccination as our model system, we will answer for the first time, a fundamental biological question within the context of antibody responses - what is the link between genotype (antibody repertoire) and phenotype (serum antibodies)? We will expand upon this approach for improved rational vaccine design by quantitatively determining the impact of a comprehensive set of subunit vaccination parameters on complete antibody landscapes. Finally, we will develop advanced bioinformatic methods to discover immunodiagnostics based on antibody repertoire sequences. In summary, this proposal lays the foundation for fundamentally new approaches in the quantitative analysis of antibody responses, which long-term will promote the development of next-generation vaccines and immunodiagnostics.
Summary
Vaccines and immunodiagnostics have been vital for public health and medicine, however a quantitative molecular understanding of vaccine-induced antibody responses is lacking. Antibody research is currently going through a big-data driven revolution, largely due to progress in next-generation sequencing (NGS) and bioinformatic analysis of antibody repertoires. A main advantage of high-throughput antibody repertoire analysis is that it provides a wealth of quantitative information not possible with other classical methods of antibody analysis (i.e., serum titers); this information includes: clonal distribution and diversity, somatic hypermutation patterns, and lineage tracing. In preliminary work my group has established standardized methods for antibody repertoire NGS, including an experimental-bioinformatic pipeline for error and bias correction that enables highly accurate repertoire sequencing and analysis. The overall goal of this proposal will be to apply high-throughput antibody repertoire analysis for quantitative vaccine profiling and discovery of next-generation immunodiagnostics. Using mouse subunit vaccination as our model system, we will answer for the first time, a fundamental biological question within the context of antibody responses - what is the link between genotype (antibody repertoire) and phenotype (serum antibodies)? We will expand upon this approach for improved rational vaccine design by quantitatively determining the impact of a comprehensive set of subunit vaccination parameters on complete antibody landscapes. Finally, we will develop advanced bioinformatic methods to discover immunodiagnostics based on antibody repertoire sequences. In summary, this proposal lays the foundation for fundamentally new approaches in the quantitative analysis of antibody responses, which long-term will promote the development of next-generation vaccines and immunodiagnostics.
Max ERC Funding
1 492 586 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym Antivessel-T-Cells
Project Development of Vascular-Disrupting Lymphocyte Therapy for Tumours
Researcher (PI) Georgios Coukos
Host Institution (HI) CENTRE HOSPITALIER UNIVERSITAIRE VAUDOIS
Call Details Advanced Grant (AdG), LS7, ERC-2012-ADG_20120314
Summary T cell engineering with chimeric antigen receptors has opened the door to effective immunotherapy. CARs are fusion genes encoding receptors whose extracellular domain comprises a single chain variable fragment (scFv) antibody that binds to a tumour surface epitope, while the intracellular domain comprises the signalling module of CD3ζ along with powerful costimulatory domains (e.g. CD28 and/or 4-1BB). CARs are a major breakthrough, since they allow bypassing HLA restrictions or loss, and they can incorporate potent costimulatory signals tailored to optimize T cell function. However, solid tumours present challenges, since they are often genetically unstable, and the tumour microenvironment impedes T cell function. The tumour vasculature is a much more stable and accessible target, and its disruption has catastrophic consequences for tumours. Nevertheless, the lack of affinity reagents has impeded progress in this area. The objectives of this proposal are to develop the first potent and safe tumour vascular-disrupting tumour immunotherapy using scFv’s and CARs uniquely available in my laboratory.
I propose to use these innovative CARs to understand for the first time the molecular mechanisms underlying the interactions between anti-vascular CAR-T cells and tumour endothelium, and exploit them to maximize tumour vascular destruction. I also intend to employ innovative engineering approaches to minimize the chance of reactivity against normal vasculature. Lastly, I propose to manipulate the tumour damage mechanisms ensuing anti-vascular therapy, to maximize tumour rejection through immunomodulation. We are poised to elucidate critical interactions between tumour endothelium and anti-vascular T cells, and bring to bear cancer therapy of unparalleled power. The impact of this work could be transforming, given the applicability of tumour-vascular disruption across most common tumour types.
Summary
T cell engineering with chimeric antigen receptors has opened the door to effective immunotherapy. CARs are fusion genes encoding receptors whose extracellular domain comprises a single chain variable fragment (scFv) antibody that binds to a tumour surface epitope, while the intracellular domain comprises the signalling module of CD3ζ along with powerful costimulatory domains (e.g. CD28 and/or 4-1BB). CARs are a major breakthrough, since they allow bypassing HLA restrictions or loss, and they can incorporate potent costimulatory signals tailored to optimize T cell function. However, solid tumours present challenges, since they are often genetically unstable, and the tumour microenvironment impedes T cell function. The tumour vasculature is a much more stable and accessible target, and its disruption has catastrophic consequences for tumours. Nevertheless, the lack of affinity reagents has impeded progress in this area. The objectives of this proposal are to develop the first potent and safe tumour vascular-disrupting tumour immunotherapy using scFv’s and CARs uniquely available in my laboratory.
I propose to use these innovative CARs to understand for the first time the molecular mechanisms underlying the interactions between anti-vascular CAR-T cells and tumour endothelium, and exploit them to maximize tumour vascular destruction. I also intend to employ innovative engineering approaches to minimize the chance of reactivity against normal vasculature. Lastly, I propose to manipulate the tumour damage mechanisms ensuing anti-vascular therapy, to maximize tumour rejection through immunomodulation. We are poised to elucidate critical interactions between tumour endothelium and anti-vascular T cells, and bring to bear cancer therapy of unparalleled power. The impact of this work could be transforming, given the applicability of tumour-vascular disruption across most common tumour types.
Max ERC Funding
2 500 000 €
Duration
Start date: 2013-08-01, End date: 2018-07-31
Project acronym ARMOR-T
Project Armoring multifunctional T cells for cancer therapy
Researcher (PI) Sebastian Kobold
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary Adoptive T cell therapy (ACT) is a powerful approach to treat even advanced cancer diseases where poor prognosis calls for innovative treatments. However ACT is critically limited by insufficient T cell infiltration into the tumor, T cell activation at the tumor site and local T cell suppression. Few advances have been made in the field to tackle these limitations besides increasing T cell activation. My group has focussed on these unaddressed issues but came to realise that tackling these one by one will not be sufficient. I have developed a panel of unpublished chemokine receptors and innovative modular antibody-activated receptors which have the potential to overcome the limitations of ACT against solid tumors. This ground-breaking portfolio places my group in the unique position to address combination of synergistic receptors and enable cellular therapies in previously unsuccessful indications. My project will provide the rationale for provision of an effective cancer treatment. The goal is to develop the next generation of ACT through T cell engineering both by forced expression of migratory and activating receptors and simultaneous deletion of immune suppressive molecules by gene editing. ARMOR-T will provide the basis for further preclinical and clinical development of a pioneering cellular product devoid of the limitations of available products to date. I will prove 1) synergy between migratory and modular activating receptors, 2) feasibility to integrate gene editing into a T cell expansion protocol, 3) synergy between gene editing, migratory and modular receptors and 4) efficacy, safety and mode of action. The main work of the project will be carried out in models of pancreatic cancer. The ARMOR-T platform will subsequently be translated to other cancer entities where response to ACT is likely such as melanoma, breast or colon cancer, providing less toxic and more effective therapies to otherwise untreatable disease.
Summary
Adoptive T cell therapy (ACT) is a powerful approach to treat even advanced cancer diseases where poor prognosis calls for innovative treatments. However ACT is critically limited by insufficient T cell infiltration into the tumor, T cell activation at the tumor site and local T cell suppression. Few advances have been made in the field to tackle these limitations besides increasing T cell activation. My group has focussed on these unaddressed issues but came to realise that tackling these one by one will not be sufficient. I have developed a panel of unpublished chemokine receptors and innovative modular antibody-activated receptors which have the potential to overcome the limitations of ACT against solid tumors. This ground-breaking portfolio places my group in the unique position to address combination of synergistic receptors and enable cellular therapies in previously unsuccessful indications. My project will provide the rationale for provision of an effective cancer treatment. The goal is to develop the next generation of ACT through T cell engineering both by forced expression of migratory and activating receptors and simultaneous deletion of immune suppressive molecules by gene editing. ARMOR-T will provide the basis for further preclinical and clinical development of a pioneering cellular product devoid of the limitations of available products to date. I will prove 1) synergy between migratory and modular activating receptors, 2) feasibility to integrate gene editing into a T cell expansion protocol, 3) synergy between gene editing, migratory and modular receptors and 4) efficacy, safety and mode of action. The main work of the project will be carried out in models of pancreatic cancer. The ARMOR-T platform will subsequently be translated to other cancer entities where response to ACT is likely such as melanoma, breast or colon cancer, providing less toxic and more effective therapies to otherwise untreatable disease.
Max ERC Funding
1 636 710 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym BIO-IRT
Project Biologically individualized, model-based radiotherapy on the basis of multi-parametric molecular tumour profiling
Researcher (PI) Daniela Thorwarth
Host Institution (HI) EBERHARD KARLS UNIVERSITAET TUEBINGEN
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary High precision radiotherapy (RT) allows extremely flexible tumour treatments achieving highly conformal radiation doses while sparing surrounding organs at risk. Nevertheless, failure rates of up to 50% are reported for head and neck cancer (HNC) due to radiation resistance induced by pathophysiologic factors such as hypoxia and other clinical factors as HPV-status, stage and tumour volume.
This project aims at developing a multi-parametric model for individualized RT (iRT) dose prescriptions in HNC based on biological markers and functional PET/MR imaging. This project goes far beyond current research standards and clinical practice as it aims for establishing hypoxia PET and f-MRI as well as biological markers in HNC as a role model for a novel concept from anatomy-based to biologically iRT.
During this project, a multi-parametric model will be developed on a preclinical basis that combines biological markers such as different oncogenes and hypoxia gene classifier with functional PET/MR imaging, such as FMISO PET in combination with different f-MRI techniques, like DW-, DCE- and BOLD-MRI in addition to MR spectroscopy. The ultimate goal of this project is a multi-parametric model to predict therapy outcome and guide iRT.
In a second part, a clinical study will be carried out to validate the preclinical model in patients. Based on the most informative radiobiological and imaging parameters as identified during the pre-clinical phase, biological markers and advanced PET/MR imaging will be evaluated in terms of their potential for iRT dose prescription.
Successful development of a model for biologically iRT prescription on the basis of multi-parametric molecular profiling would provide a unique basis for personalized cancer treatment. A validated multi-parametric model for RT outcome would represent a paradigm shift from anatomy-based to biologically iRT concepts with the ultimate goal of improving cancer cure rates.
Summary
High precision radiotherapy (RT) allows extremely flexible tumour treatments achieving highly conformal radiation doses while sparing surrounding organs at risk. Nevertheless, failure rates of up to 50% are reported for head and neck cancer (HNC) due to radiation resistance induced by pathophysiologic factors such as hypoxia and other clinical factors as HPV-status, stage and tumour volume.
This project aims at developing a multi-parametric model for individualized RT (iRT) dose prescriptions in HNC based on biological markers and functional PET/MR imaging. This project goes far beyond current research standards and clinical practice as it aims for establishing hypoxia PET and f-MRI as well as biological markers in HNC as a role model for a novel concept from anatomy-based to biologically iRT.
During this project, a multi-parametric model will be developed on a preclinical basis that combines biological markers such as different oncogenes and hypoxia gene classifier with functional PET/MR imaging, such as FMISO PET in combination with different f-MRI techniques, like DW-, DCE- and BOLD-MRI in addition to MR spectroscopy. The ultimate goal of this project is a multi-parametric model to predict therapy outcome and guide iRT.
In a second part, a clinical study will be carried out to validate the preclinical model in patients. Based on the most informative radiobiological and imaging parameters as identified during the pre-clinical phase, biological markers and advanced PET/MR imaging will be evaluated in terms of their potential for iRT dose prescription.
Successful development of a model for biologically iRT prescription on the basis of multi-parametric molecular profiling would provide a unique basis for personalized cancer treatment. A validated multi-parametric model for RT outcome would represent a paradigm shift from anatomy-based to biologically iRT concepts with the ultimate goal of improving cancer cure rates.
Max ERC Funding
1 370 799 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym BioProbe
Project "VERTICAL MICROFLUIDIC PROBE: A nanoliter ""Swiss army knife"" for chemistry and physics at biological interfaces"
Researcher (PI) Govindkrishna Govind Kaigala
Host Institution (HI) IBM RESEARCH GMBH
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary Life is fundamentally characterised by order, compartmentalisation and biochemical reactions, which occurs at the right place right time – within, on the surface and between cells. Only a proportion of life processes can be addressed with contemporary approaches like liquid encapsulations (e.g. droplets) or engineering compartments (e.g. scaffolds). I believe these approaches are severely limited. I am convinced that a technique to study, work and locally probe adherent cells & tissues at micrometer distances from cell surfaces in “open space” would represent a major advance for the biology of biointerfaces. I therefore propose a non-contact, scanning technology, which spatially confines nanoliter volumes of chemicals for interacting with cells at the µm-length scale. This technology called the vertical microfluidic probe (vMFP) – that I developed at IBM-Zurich – shapes liquid on surfaces hydrodynamically and is compatible with samples on Petri dishes & microtiter plates. The project is organized in 4 themes:
(1) Advancing the vMFP by understanding the interaction of liquid flows with biointerfaces, integrating functional elements (e.g. heaters/electrodes, cell traps) & precision control.
(2) Developing a higher resolution method to stain tissue sections for multiple markers & better quality information.
(3) Retrieving rare elements such as circulating tumor cells from biologically diverse libraries.
(4) Patterning cells for applications in regenerative medicine.
Since cells & tissues will no longer be limited by closed systems, the vMFP will enable a completely new range of experiments to be performed in a highly interactive, versatile & precise manner – this approach departs from classical “closed” microfluidics. It is very likely that such a tool by providing multifunctional capabilities akin to the proverbial ‘Swiss army knife’ will be a unique facilitator for investigations of previously unapproachable problems in cell biology & the life science.
Summary
Life is fundamentally characterised by order, compartmentalisation and biochemical reactions, which occurs at the right place right time – within, on the surface and between cells. Only a proportion of life processes can be addressed with contemporary approaches like liquid encapsulations (e.g. droplets) or engineering compartments (e.g. scaffolds). I believe these approaches are severely limited. I am convinced that a technique to study, work and locally probe adherent cells & tissues at micrometer distances from cell surfaces in “open space” would represent a major advance for the biology of biointerfaces. I therefore propose a non-contact, scanning technology, which spatially confines nanoliter volumes of chemicals for interacting with cells at the µm-length scale. This technology called the vertical microfluidic probe (vMFP) – that I developed at IBM-Zurich – shapes liquid on surfaces hydrodynamically and is compatible with samples on Petri dishes & microtiter plates. The project is organized in 4 themes:
(1) Advancing the vMFP by understanding the interaction of liquid flows with biointerfaces, integrating functional elements (e.g. heaters/electrodes, cell traps) & precision control.
(2) Developing a higher resolution method to stain tissue sections for multiple markers & better quality information.
(3) Retrieving rare elements such as circulating tumor cells from biologically diverse libraries.
(4) Patterning cells for applications in regenerative medicine.
Since cells & tissues will no longer be limited by closed systems, the vMFP will enable a completely new range of experiments to be performed in a highly interactive, versatile & precise manner – this approach departs from classical “closed” microfluidics. It is very likely that such a tool by providing multifunctional capabilities akin to the proverbial ‘Swiss army knife’ will be a unique facilitator for investigations of previously unapproachable problems in cell biology & the life science.
Max ERC Funding
1 488 600 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym BIOSENSORIMAGING
Project Hyperpolarized Biosensors in Molecular Imaging
Researcher (PI) Leif Schröder
Host Institution (HI) FORSCHUNGSVERBUND BERLIN EV
Call Details Starting Grant (StG), LS7, ERC-2009-StG
Summary Xenon biosensors have an outstanding potential to increase the significance of magnetic resonance imaging (MRI) in molecular imaging and to combine the advantages of MRI with the high sensitivity of hyperpolarized Xe-129 and the specificity of a functionalized contrast agent. Based on new detection schemes (Hyper-CEST method) in Xe MRI, this novel concept in molecular diagnostics will be made available for biomedical applications. The advancement focuses on high-sensitivity in vitro diagnostics for localization of tumour cells in cell cultures and first demonstrations on animal models based on a transferrin-functionalized biosensor. Such a sensor will enable detection of subcutaneous tumours at high sensitivity without any background signal. More detailed work on the different available Hyper-CEST contrast parameters focuses on an absolute quantification of new molecular markers that will improve non-invasive tumour diagnostics significantly. NMR detection of functionalized Xe biosensors have the potential to close the sensitivity gap between modalities of nuclear medicine like PET/SPECT and MRI without using ionizing radiation or making compromises in penetration depth like in optical methods.
Summary
Xenon biosensors have an outstanding potential to increase the significance of magnetic resonance imaging (MRI) in molecular imaging and to combine the advantages of MRI with the high sensitivity of hyperpolarized Xe-129 and the specificity of a functionalized contrast agent. Based on new detection schemes (Hyper-CEST method) in Xe MRI, this novel concept in molecular diagnostics will be made available for biomedical applications. The advancement focuses on high-sensitivity in vitro diagnostics for localization of tumour cells in cell cultures and first demonstrations on animal models based on a transferrin-functionalized biosensor. Such a sensor will enable detection of subcutaneous tumours at high sensitivity without any background signal. More detailed work on the different available Hyper-CEST contrast parameters focuses on an absolute quantification of new molecular markers that will improve non-invasive tumour diagnostics significantly. NMR detection of functionalized Xe biosensors have the potential to close the sensitivity gap between modalities of nuclear medicine like PET/SPECT and MRI without using ionizing radiation or making compromises in penetration depth like in optical methods.
Max ERC Funding
1 848 600 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym BREATHE
Project Biochemically modified messenger RNA encoding nucleases for in vivo gene correction of severe inherited lung diseases
Researcher (PI) Michael Kormann
Host Institution (HI) EBERHARD KARLS UNIVERSITAET TUEBINGEN
Call Details Starting Grant (StG), LS7, ERC-2014-STG
Summary Surfactant Protein B (SP-B) deficiency and Cystic Fibrosis (CF) are severe, fatal inherited diseases affecting the lungs of ten thousands of people, for which there is currently no available cure. Although gene therapy is a promising therapeutic approach, various technical problems, including numerous physical and immune-mediated barriers, have prevented successful application to date. My recent studies were the first to demonstrate the life-saving efficacy of repeated pulmonary delivery of chemically modified messenger RNA (mRNA) in a mouse model of congenital SP-B deficiency. By incorporating balanced amounts of modified nucleotides to mimic endogenous transcripts, I developed a safe and therapeutically efficient vehicle for lung transfection that eliminates the risk of genomic integration commonly associated with DNA-based vectors. I also assessed the delivery of mRNA-encoded site-specific nucleases to the lung to facilitate targeted gene correction of the underlying disease-causing mutations. In comprehensive studies, we show that a single application of nucleases encoded by nucleotide-modified RNA (nec-mRNA) can generate in vivo correction of terminally differentiated alveolar type II cells, which more than quadrupled the life span of SP-B deficient mice. Together with my working group, I aim to further develop this technology to enhance the efficiency and safety of nec-mRNA-mediated in vivo lung stem cell targeting, providing an ultimate cure by permanent correction. Specifically, we will test this approach in humanized mouse models of SP-B deficiency and CF. Developing and genetically engineering humanized models in vivo will be a critical step towards the safe translation of mRNA based nuclease technology to the clinic. With my competitive edge in lung-transfection technology and strong data, I feel that my group is uniquely suited to achieve these goals and to make a highly valuable contribution to the development of an efficient treatment.
Summary
Surfactant Protein B (SP-B) deficiency and Cystic Fibrosis (CF) are severe, fatal inherited diseases affecting the lungs of ten thousands of people, for which there is currently no available cure. Although gene therapy is a promising therapeutic approach, various technical problems, including numerous physical and immune-mediated barriers, have prevented successful application to date. My recent studies were the first to demonstrate the life-saving efficacy of repeated pulmonary delivery of chemically modified messenger RNA (mRNA) in a mouse model of congenital SP-B deficiency. By incorporating balanced amounts of modified nucleotides to mimic endogenous transcripts, I developed a safe and therapeutically efficient vehicle for lung transfection that eliminates the risk of genomic integration commonly associated with DNA-based vectors. I also assessed the delivery of mRNA-encoded site-specific nucleases to the lung to facilitate targeted gene correction of the underlying disease-causing mutations. In comprehensive studies, we show that a single application of nucleases encoded by nucleotide-modified RNA (nec-mRNA) can generate in vivo correction of terminally differentiated alveolar type II cells, which more than quadrupled the life span of SP-B deficient mice. Together with my working group, I aim to further develop this technology to enhance the efficiency and safety of nec-mRNA-mediated in vivo lung stem cell targeting, providing an ultimate cure by permanent correction. Specifically, we will test this approach in humanized mouse models of SP-B deficiency and CF. Developing and genetically engineering humanized models in vivo will be a critical step towards the safe translation of mRNA based nuclease technology to the clinic. With my competitive edge in lung-transfection technology and strong data, I feel that my group is uniquely suited to achieve these goals and to make a highly valuable contribution to the development of an efficient treatment.
Max ERC Funding
1 497 125 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym BRuSH
Project Oral bacteria as determinants for respiratory health
Researcher (PI) Randi BERTELSEN
Host Institution (HI) UNIVERSITETET I BERGEN
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary The oral cavity is the gateway to the lower respiratory tract, and oral bacteria are likely to play a role in lung health. This may be the case for pathogens as well as commensal bacteria and the balance between species. The oral bacterial community of patients with periodontitis is dominated by gram-negative bacteria and a higher lipopolysaccharide (LPS) activity than in healthy microbiota. Furthermore, bacteria with especially potent pro-inflammatory LPS have been shown to be more common in the lungs of asthmatic than in healthy individuals. The working hypothesis of BRuSH is that microbiome communities dominated by LPS-producing bacteria which induce a particularly strong pro-inflammatory immune response in the host, will have a negative effect on respiratory health. I will test this hypothesis in two longitudinally designed population-based lung health studies. I aim to identify whether specific bacterial composition and types of LPS producing bacteria in oral and dust samples predict lung function and respiratory health over time; and if the different types of LPS-producing bacteria affect LPS in saliva saliva and dust. BRuSH will apply functional genome annotation that can assign biological significance to raw bacterial DNA sequences. With this bioinformatics tool I will cluster microbiome data into various LPS-producers: bacteria with LPS with strong inflammatory effects and others with weak- or antagonistic effects. The epidemiological studies will be supported by mice-models of asthma and cell assays of human bronchial epithelial cells, by exposing mice and bronchial cells to chemically synthesized Lipid A (the component that drive the LPS-induced immune responses) of various potency. The goal of BRuSH is to prove a causal relationship between oral microbiome and lung health, and gain knowledge that will enable us to make oral health a feasible target for intervention programs aimed at optimizing lung health and preventing respiratory disease.
Summary
The oral cavity is the gateway to the lower respiratory tract, and oral bacteria are likely to play a role in lung health. This may be the case for pathogens as well as commensal bacteria and the balance between species. The oral bacterial community of patients with periodontitis is dominated by gram-negative bacteria and a higher lipopolysaccharide (LPS) activity than in healthy microbiota. Furthermore, bacteria with especially potent pro-inflammatory LPS have been shown to be more common in the lungs of asthmatic than in healthy individuals. The working hypothesis of BRuSH is that microbiome communities dominated by LPS-producing bacteria which induce a particularly strong pro-inflammatory immune response in the host, will have a negative effect on respiratory health. I will test this hypothesis in two longitudinally designed population-based lung health studies. I aim to identify whether specific bacterial composition and types of LPS producing bacteria in oral and dust samples predict lung function and respiratory health over time; and if the different types of LPS-producing bacteria affect LPS in saliva saliva and dust. BRuSH will apply functional genome annotation that can assign biological significance to raw bacterial DNA sequences. With this bioinformatics tool I will cluster microbiome data into various LPS-producers: bacteria with LPS with strong inflammatory effects and others with weak- or antagonistic effects. The epidemiological studies will be supported by mice-models of asthma and cell assays of human bronchial epithelial cells, by exposing mice and bronchial cells to chemically synthesized Lipid A (the component that drive the LPS-induced immune responses) of various potency. The goal of BRuSH is to prove a causal relationship between oral microbiome and lung health, and gain knowledge that will enable us to make oral health a feasible target for intervention programs aimed at optimizing lung health and preventing respiratory disease.
Max ERC Funding
1 499 938 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym CAN-IT-BARRIERS
Project Disruption of systemic and microenvironmental barriers to immunotherapy of antigenic tumors
Researcher (PI) Douglas HANAHAN
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary The frontier in cancer therapy of orchestrating the immune system to attack tumors is producing unprecedented survival benefit in some patients. The corollary is lack of efficacy both in ostensibly responsive tumor types as well as others that are mostly non-responsive. The basis lies in pre-existing and adaptive resistance mechanisms that circumvent induction of tumor-reactive cytotoxic T cells (CTLs) capable of infiltrating solid tumors and eliminating cancer cells. A priori, cancers induced by expression of human papillomavirus oncogenes should be responsive to immunotherapy: these cancers encode immunogenic neo-antigens – the oncoproteins E6/7 – necessary for their manifestation. Rather, such tumors are poorly responsive to immunotherapies. Results from my lab and others using mouse models of HPV-induced cancer have established an actionable hypothesis: during tumorigenesis, such tumors erect multiple barriers to the induction, infiltration, and killing of cancer cells by tumor antigen-reactive CTLs. These include overarching systemic antigen-nonspecific immunosuppression mediated by expanded populations of myeloid cells in spleen and lymph nodes, complemented by immune response-impairing barriers operative in the tumor microenvironment. A spectrum of models will probe these barriers, genetically and pharmacologically, establishing their functional importance, alone and in concert. A major focus will be on how oncogene-expressing keratinocytes elicit a marked expansion of immunosuppressive myeloid cells in spleen and lymph nodes, and how these myeloid cells in turn inhibit development and activation of CD8 T cells and antigen-presenting dendritic cells. Then we’ll assess the therapeutic potential of barrier-breaking strategies combined with immuno-stimulatory modalities. This project will deliver new knowledge about multi-faceted barriers to immunotherapy in these refractory cancers, helping lay the groundwork for efficacious immunotherapy.
Summary
The frontier in cancer therapy of orchestrating the immune system to attack tumors is producing unprecedented survival benefit in some patients. The corollary is lack of efficacy both in ostensibly responsive tumor types as well as others that are mostly non-responsive. The basis lies in pre-existing and adaptive resistance mechanisms that circumvent induction of tumor-reactive cytotoxic T cells (CTLs) capable of infiltrating solid tumors and eliminating cancer cells. A priori, cancers induced by expression of human papillomavirus oncogenes should be responsive to immunotherapy: these cancers encode immunogenic neo-antigens – the oncoproteins E6/7 – necessary for their manifestation. Rather, such tumors are poorly responsive to immunotherapies. Results from my lab and others using mouse models of HPV-induced cancer have established an actionable hypothesis: during tumorigenesis, such tumors erect multiple barriers to the induction, infiltration, and killing of cancer cells by tumor antigen-reactive CTLs. These include overarching systemic antigen-nonspecific immunosuppression mediated by expanded populations of myeloid cells in spleen and lymph nodes, complemented by immune response-impairing barriers operative in the tumor microenvironment. A spectrum of models will probe these barriers, genetically and pharmacologically, establishing their functional importance, alone and in concert. A major focus will be on how oncogene-expressing keratinocytes elicit a marked expansion of immunosuppressive myeloid cells in spleen and lymph nodes, and how these myeloid cells in turn inhibit development and activation of CD8 T cells and antigen-presenting dendritic cells. Then we’ll assess the therapeutic potential of barrier-breaking strategies combined with immuno-stimulatory modalities. This project will deliver new knowledge about multi-faceted barriers to immunotherapy in these refractory cancers, helping lay the groundwork for efficacious immunotherapy.
Max ERC Funding
2 500 000 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym CLLCLONE
Project Harnessing clonal evolution in chronic lymphocytic leukemia
Researcher (PI) Davide ROSSI
Host Institution (HI) FONDAZIONE PER L'ISTITUTO ONCOLOGICO DI RICERCA (IOR)
Call Details Consolidator Grant (CoG), LS7, ERC-2017-COG
Summary Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is addicted of interactions with the microenvironment. The B-cell receptor (BCR) is one of the most important surface molecules that CLL cells use to gain oncogenic signals from the microenvironment. The critical role of BCR signaling for the pathogenesis of CLL is supported by the therapeutic success of ibrutinib, a targeted agent that disrupts the BCR pathway. Beside microenvironment-promoted oncogenic signals, the biology of CLL is also driven by molecular lesions and clonal evolution, that mark CLL progression and treatment resistance. The interconnection between microenvironment-promoted oncogenic signals and clonal evolution has been postulated in CLL but never proven because of the lack of suitable ex vivo models. Ibrutinib allows the unprecedented opportunity of assessing the contribution of cell signaling to cancer clonal evolution directly in vivo in patients. The project working hypothesis is that mutation- and selection-driven clonal evolution is promoted by microenvironment-induced signals, including those propagated from the BCR. According to this hypothesis: i) BCR signaling inhibition due to ibrutinib should stop clonal evolution; while ii) acquisition of by-pass mechanisms that keep ongoing signaling should promote mutation and selection despite BCR inhibition, thus favoring CLL clonal evolution and ibrutinib resistance. In this scenario, the combination of ibrutinib with drugs that overcome by-pass mechanisms could prevent clonal evolution, thus improving treatment efficacy and patient outcome. In order to address our working hypothesis, we will take advantage of clinical trial and co-clinical trial samples to monitor signaling and clonal evolution under ibrutinib and ibrutinib-based combination treatments.
Summary
Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is addicted of interactions with the microenvironment. The B-cell receptor (BCR) is one of the most important surface molecules that CLL cells use to gain oncogenic signals from the microenvironment. The critical role of BCR signaling for the pathogenesis of CLL is supported by the therapeutic success of ibrutinib, a targeted agent that disrupts the BCR pathway. Beside microenvironment-promoted oncogenic signals, the biology of CLL is also driven by molecular lesions and clonal evolution, that mark CLL progression and treatment resistance. The interconnection between microenvironment-promoted oncogenic signals and clonal evolution has been postulated in CLL but never proven because of the lack of suitable ex vivo models. Ibrutinib allows the unprecedented opportunity of assessing the contribution of cell signaling to cancer clonal evolution directly in vivo in patients. The project working hypothesis is that mutation- and selection-driven clonal evolution is promoted by microenvironment-induced signals, including those propagated from the BCR. According to this hypothesis: i) BCR signaling inhibition due to ibrutinib should stop clonal evolution; while ii) acquisition of by-pass mechanisms that keep ongoing signaling should promote mutation and selection despite BCR inhibition, thus favoring CLL clonal evolution and ibrutinib resistance. In this scenario, the combination of ibrutinib with drugs that overcome by-pass mechanisms could prevent clonal evolution, thus improving treatment efficacy and patient outcome. In order to address our working hypothesis, we will take advantage of clinical trial and co-clinical trial samples to monitor signaling and clonal evolution under ibrutinib and ibrutinib-based combination treatments.
Max ERC Funding
1 940 000 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym COMBIOSCOPY
Project Computational Biophotonics for Endoscopic Cancer Diagnosis and Therapy
Researcher (PI) Lena Maier-Hein
Host Institution (HI) DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Call Details Starting Grant (StG), LS7, ERC-2014-STG
Summary Key challenges in endoscopic tumor diagnosis and therapy consist of the detection and discrimination of malignant tissue as well as the precise navigation of medical instruments. Currently, a low level of sensitivity and specificity in tumor detection and lack of global orientation lead to both over- and undertreatment, tumor recurrence, intra-operative complications, and high costs. The goal of this multidisciplinary project is to revolutionize clinical endoscopic imaging based on the systematic integration of two new but independant fields of research up until this point: Biophotonics and computer-assisted interventions (COMputational BIOphotonics in endoSCOPY).
For the first time, quantitative multi-modal imaging biomarkers based on structural and functional data are being developed to enhance the physician’s view by providing information that cannot be seen with the naked eye. To this extent, white light images co-registered with multispectral optical and photoacoustic images will be processed in a combined manner to dynamically reconstruct not only the visible surface in 3D but also subsurface anatomical and functional detail such as 3D vessel topology, blood volume and oxygenation. Spatio-temporal registration of multi-modal data acquired before and during the procedure will enable (1) the highly specific local tissue classification and discrimination based on tissue shape, texture, function and radiological contrast imagery as well as (2) global context-aware instrument guidance.
This innovative approach to radiation-free real-time imaging will be implemented and evaluated by means of computer-assisted colonoscopy and laparoscopy. The potential socioeconomic impact of providing high precision minimally-invasive tumor diagnosis and therapy at low cost is extremely high.
Summary
Key challenges in endoscopic tumor diagnosis and therapy consist of the detection and discrimination of malignant tissue as well as the precise navigation of medical instruments. Currently, a low level of sensitivity and specificity in tumor detection and lack of global orientation lead to both over- and undertreatment, tumor recurrence, intra-operative complications, and high costs. The goal of this multidisciplinary project is to revolutionize clinical endoscopic imaging based on the systematic integration of two new but independant fields of research up until this point: Biophotonics and computer-assisted interventions (COMputational BIOphotonics in endoSCOPY).
For the first time, quantitative multi-modal imaging biomarkers based on structural and functional data are being developed to enhance the physician’s view by providing information that cannot be seen with the naked eye. To this extent, white light images co-registered with multispectral optical and photoacoustic images will be processed in a combined manner to dynamically reconstruct not only the visible surface in 3D but also subsurface anatomical and functional detail such as 3D vessel topology, blood volume and oxygenation. Spatio-temporal registration of multi-modal data acquired before and during the procedure will enable (1) the highly specific local tissue classification and discrimination based on tissue shape, texture, function and radiological contrast imagery as well as (2) global context-aware instrument guidance.
This innovative approach to radiation-free real-time imaging will be implemented and evaluated by means of computer-assisted colonoscopy and laparoscopy. The potential socioeconomic impact of providing high precision minimally-invasive tumor diagnosis and therapy at low cost is extremely high.
Max ERC Funding
1 499 699 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym CYTRIX
Project Engineering Cytokines for Super-Affinity Binding to Matrix in Regenerative Medicine
Researcher (PI) Jeffrey Alan Hubbell
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Advanced Grant (AdG), LS7, ERC-2013-ADG
Summary In physiological situations, the extracellular matrix (ECM) sequesters cytokines, localizes them, and modulates their signaling. Thus, physiological signaling from cytokines occurs primarily when the cytokines are interacting with the ECM. In therapeutic use of cytokines, however, this interaction and balance have not been respected; rather the growth factors are merely injected or applied as soluble molecules, perhaps in controlled release forms. This has led to modest efficacy and substantial concerns on safety. Here, we will develop a protein engineering design for second-generation cytokines to lead to their super-affinity binding to ECM molecules in the targeted tissues; this would allow application to a tissue site to yield a tight association with ECM molecules there, turning the tissue itself into a reservoir for cytokine sequestration and presentation. To accomplish this, we have undertaken preliminary work screening a library of cytokines for extraordinarily high affinity binding to a library of ECM molecules. We have thereby identified a small peptide domain within placental growth factor-2 (PlGF-2), namely PlGF-2123-144, that displays super-affinity for a number of ECM proteins. Also in preliminary work, we have demonstrated that recombinant fusion of this domain to low-affinity binding cytokines, namely VEGF-A, PDGF-BB and BMP-2, confers super-affinity binding to ECM molecules and accentuates their functionality in vivo in regenerative medicine models. In the proposed project, based on this preliminary data, we will push forward this protein engineering design, pursuing super-affinity variants of VEGF-A and PDGF-BB in chronic wounds, TGF-beta3 and CXCL11 in skin scar reduction, FGF-18 in osteoarthritic cartilage repair and CXCL12 in stem cell recruitment to ischemic cardiac muscle. Thus, we seek to demonstrate a fundamentally new concept and platform for second-generation growth factor protein engineering.
Summary
In physiological situations, the extracellular matrix (ECM) sequesters cytokines, localizes them, and modulates their signaling. Thus, physiological signaling from cytokines occurs primarily when the cytokines are interacting with the ECM. In therapeutic use of cytokines, however, this interaction and balance have not been respected; rather the growth factors are merely injected or applied as soluble molecules, perhaps in controlled release forms. This has led to modest efficacy and substantial concerns on safety. Here, we will develop a protein engineering design for second-generation cytokines to lead to their super-affinity binding to ECM molecules in the targeted tissues; this would allow application to a tissue site to yield a tight association with ECM molecules there, turning the tissue itself into a reservoir for cytokine sequestration and presentation. To accomplish this, we have undertaken preliminary work screening a library of cytokines for extraordinarily high affinity binding to a library of ECM molecules. We have thereby identified a small peptide domain within placental growth factor-2 (PlGF-2), namely PlGF-2123-144, that displays super-affinity for a number of ECM proteins. Also in preliminary work, we have demonstrated that recombinant fusion of this domain to low-affinity binding cytokines, namely VEGF-A, PDGF-BB and BMP-2, confers super-affinity binding to ECM molecules and accentuates their functionality in vivo in regenerative medicine models. In the proposed project, based on this preliminary data, we will push forward this protein engineering design, pursuing super-affinity variants of VEGF-A and PDGF-BB in chronic wounds, TGF-beta3 and CXCL11 in skin scar reduction, FGF-18 in osteoarthritic cartilage repair and CXCL12 in stem cell recruitment to ischemic cardiac muscle. Thus, we seek to demonstrate a fundamentally new concept and platform for second-generation growth factor protein engineering.
Max ERC Funding
2 368 170 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym DIAMONDCOR
Project A molecular approach to treat diabetes mellitus onset dependent coronaropathy
Researcher (PI) Rabea HINKEL
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary In Europe, 59 million patients suffer from diabetes mellitus with health costs of 142 billion Euros per year. As one of the most challenging consequences, diabetes inflicts cardiovascular disease leading to cardiomyopathy and cardiac death. A global, current aim lies in preventing cardiac complications in patients with diabetes mellitus.
In pathogenesis of diabetic cardiomyopathy, the role of microvascular processes remains largely elusive; my proposal aims at solving this key question – an impossible mission so far. As attractive therapeutic concept and overall objective, the present proposal aims at exploiting microvascular mechanisms for preventing and treating diabetic cardiomyopathy.
I will study a novel, unique transgenic pig model of diabetes mellitus combined with advanced, patient compatible molecular imaging. We pioneered distinct genetic manipulations in pigs, including adeno-associated viral vectors (AAV) for microvessel stabilization as well as AAV-based CrispR/Cas9 transduction for in vivo genome editing. Using this cutting edge technology, I could decipher an important role for microvascular capillary rarefaction in the development of diabetic cardiomyopathy in my previous work. In the present proposal, I aim at determining
1. novel, microvascular-focused therapeutic targets for diabetic cardiomyopathy
2. the effect of reduced microvascular damage on myocardial function in diabetes, both in the absence and presence of ischemia.
My approach will implement targeting microvessels as new paradigm for treating diabetic cardiomyopathy. I will identify novel therapeutic targets for tailored drug development by industry and academia. My planned work will improve the success rate of clinical trials for the benefit of patients suffering diabetic cardiomyopathy and putatively other cardiac diseases.
Summary
In Europe, 59 million patients suffer from diabetes mellitus with health costs of 142 billion Euros per year. As one of the most challenging consequences, diabetes inflicts cardiovascular disease leading to cardiomyopathy and cardiac death. A global, current aim lies in preventing cardiac complications in patients with diabetes mellitus.
In pathogenesis of diabetic cardiomyopathy, the role of microvascular processes remains largely elusive; my proposal aims at solving this key question – an impossible mission so far. As attractive therapeutic concept and overall objective, the present proposal aims at exploiting microvascular mechanisms for preventing and treating diabetic cardiomyopathy.
I will study a novel, unique transgenic pig model of diabetes mellitus combined with advanced, patient compatible molecular imaging. We pioneered distinct genetic manipulations in pigs, including adeno-associated viral vectors (AAV) for microvessel stabilization as well as AAV-based CrispR/Cas9 transduction for in vivo genome editing. Using this cutting edge technology, I could decipher an important role for microvascular capillary rarefaction in the development of diabetic cardiomyopathy in my previous work. In the present proposal, I aim at determining
1. novel, microvascular-focused therapeutic targets for diabetic cardiomyopathy
2. the effect of reduced microvascular damage on myocardial function in diabetes, both in the absence and presence of ischemia.
My approach will implement targeting microvessels as new paradigm for treating diabetic cardiomyopathy. I will identify novel therapeutic targets for tailored drug development by industry and academia. My planned work will improve the success rate of clinical trials for the benefit of patients suffering diabetic cardiomyopathy and putatively other cardiac diseases.
Max ERC Funding
1 490 529 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym DNA-AMP
Project DNA Adduct Molecular Probes: Elucidating the Diet-Cancer Connection at Chemical Resolution
Researcher (PI) Shana Jocette Sturla
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Bulky DNA adducts formed from chemical carcinogens dictate structure, reactivity, and mechanism of chemical-biological reactions; therefore, their identification is central to evaluating and mitigating cancer risk. Natural food components, or others associated with certain food preparations or metabolic conversions, initiate potentially damaging genetic mutations after forming DNA adducts, which contribute critically to carcinogenesis, despite the fact that they are typically repaired biochemically and they are formed at extremely low levels. This situation places significant limitations on our ability to understand the role of formation, repair, and mutagenesis on the basis of the complex DNA reactivity profiles of food components. The long-term goals of this research are to contribute basic knowledge and advanced experimental tools required to understand, on the basis of chemical structure, the contributions of chronic, potentially adverse, dietary chemical carcinogen exposure to cancer development. It is proposed that a new class of synthetic nucleosides, devised on the basis of preliminary discoveries made in the independent laboratory of the applicant, will serve as molecular probes for bulky DNA adducts and can be effectively used to study and AMPlify, i.e. as a sensitive diagnostic tool, low levels of chemically-specific modes of DNA damage. The proposed research is a chemical biology-based approach to the study of carcinogenesis. Experiments involve chemical synthesis, thermodynamic and kinetic characterization DNA-DNA and enzyme-DNA interactions, and nanoparticle-based molecular probes. The proposal describes a potentially ground-breaking approach for profiling the biological reactivities of chemical carcinogens, and we expect to gain fundamental knowledge and chemical tools that can contribute to the prevention of diseases influenced by gene-environment interactions.
Summary
Bulky DNA adducts formed from chemical carcinogens dictate structure, reactivity, and mechanism of chemical-biological reactions; therefore, their identification is central to evaluating and mitigating cancer risk. Natural food components, or others associated with certain food preparations or metabolic conversions, initiate potentially damaging genetic mutations after forming DNA adducts, which contribute critically to carcinogenesis, despite the fact that they are typically repaired biochemically and they are formed at extremely low levels. This situation places significant limitations on our ability to understand the role of formation, repair, and mutagenesis on the basis of the complex DNA reactivity profiles of food components. The long-term goals of this research are to contribute basic knowledge and advanced experimental tools required to understand, on the basis of chemical structure, the contributions of chronic, potentially adverse, dietary chemical carcinogen exposure to cancer development. It is proposed that a new class of synthetic nucleosides, devised on the basis of preliminary discoveries made in the independent laboratory of the applicant, will serve as molecular probes for bulky DNA adducts and can be effectively used to study and AMPlify, i.e. as a sensitive diagnostic tool, low levels of chemically-specific modes of DNA damage. The proposed research is a chemical biology-based approach to the study of carcinogenesis. Experiments involve chemical synthesis, thermodynamic and kinetic characterization DNA-DNA and enzyme-DNA interactions, and nanoparticle-based molecular probes. The proposal describes a potentially ground-breaking approach for profiling the biological reactivities of chemical carcinogens, and we expect to gain fundamental knowledge and chemical tools that can contribute to the prevention of diseases influenced by gene-environment interactions.
Max ERC Funding
1 500 000 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym DrugsInPregnancy
Project Effects of Medication Use in Pregnancy on Infant Neurodevelopment
Researcher (PI) Hedvig Marie Egeland Nordeng
Host Institution (HI) UNIVERSITETET I OSLO
Call Details Starting Grant (StG), LS7, ERC-2014-STG
Summary Currently, thousands of pregnant women in the EU and worldwide are being increasingly prescribed medications for which we do not have sufficient information on fetal safety. I hypothesize that our current understanding of safety pharmacology is oversimplified and that medication prescribed during pregnancy may play an unrecognized role in the development of neurodevelopmental disorders.
In this research proposal we have the unique opportunity to use a large population-based birth cohort including over 100 000 mother-child pairs and biological data to study how medications may act on the offspring. This offers novel and innovative pharmaceutical insight into the safety of medications.
By linking several nationwide registries (National Prescription Data Base, Norwegian Patient Registry, Medical Birth Registry) to a population-based birth cohort (n=108 000) we specifically aim to 1) estimate the effect of prenatal exposure to psychotropics and analgesics on neurodevelopment in young children using a range of methodological approaches to strengthen causal inference.
With these data made available, we will 2) determine whether fetal exposure to specific medications results in epigenetic events (i.e. changes in DNA methylation) in the child, and 3) determine whether such changes increase the risks of neurodevelopmental disorders in childhood.
The recent availability of large scale human data, possibility of register linkages and genome-wide mapping of DNA methylation at affordable costs makes this research proposal now possible. The size and richness of data including over hundred thousand pregnancies and existence of biological material makes this project unique. The final outcome will be fundamentally new knowledge about how medications affect the developing unborn child and will open up new horizons and opportunities for future research in a new field of “pharmaco-epigenetics” and enhance our understanding of origins of neurodevelopmental disorders.
Summary
Currently, thousands of pregnant women in the EU and worldwide are being increasingly prescribed medications for which we do not have sufficient information on fetal safety. I hypothesize that our current understanding of safety pharmacology is oversimplified and that medication prescribed during pregnancy may play an unrecognized role in the development of neurodevelopmental disorders.
In this research proposal we have the unique opportunity to use a large population-based birth cohort including over 100 000 mother-child pairs and biological data to study how medications may act on the offspring. This offers novel and innovative pharmaceutical insight into the safety of medications.
By linking several nationwide registries (National Prescription Data Base, Norwegian Patient Registry, Medical Birth Registry) to a population-based birth cohort (n=108 000) we specifically aim to 1) estimate the effect of prenatal exposure to psychotropics and analgesics on neurodevelopment in young children using a range of methodological approaches to strengthen causal inference.
With these data made available, we will 2) determine whether fetal exposure to specific medications results in epigenetic events (i.e. changes in DNA methylation) in the child, and 3) determine whether such changes increase the risks of neurodevelopmental disorders in childhood.
The recent availability of large scale human data, possibility of register linkages and genome-wide mapping of DNA methylation at affordable costs makes this research proposal now possible. The size and richness of data including over hundred thousand pregnancies and existence of biological material makes this project unique. The final outcome will be fundamentally new knowledge about how medications affect the developing unborn child and will open up new horizons and opportunities for future research in a new field of “pharmaco-epigenetics” and enhance our understanding of origins of neurodevelopmental disorders.
Max ERC Funding
1 499 439 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym DYNAMIT
Project Deep Tissue Optoacoustic Imaging for Tracking of Dynamic Molecular and Functional Events
Researcher (PI) Daniel Razansky
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary The ability to visualize biological processes in living organisms continuously, instead of at discrete time points, holds a great promise for studies of functional and molecular events, disease progression and treatment monitoring. Optical spectrum is particularly attractive for biological interrogations as it can impart highly versatile contrast of cellular and sub-cellular function as well as employ highly specific contrast agents and markers not available for other modalities. However, technical limitations arising from intense light scattering in living tissues bound the main-stream of high resolution optical imaging applications to microscopic studies at shallow depths that do not allow the exploration of the full potential of novel classes of agents for volumetric imaging of entire organs, small animals or human tissues.
To overcome limitations of the current imaging techniques, this proposal aims to develop a novel high performance optoacoustic imaging technology and explore its groundbreaking potential for neuroimaging and monitoring of cardiovascular disease. I will undertake a substantial technological step that will bring optoacoustic imaging to a real time (video rate) high resolution performance level the like of which has not existed so far. The resulting technique will be able to image several millimeters to centimeters into living small animals and potentially humans, with both high spatial resolution and sensitivity, being independent of photon scattering. This will make it suitable for attaining high dynamic contrast in intact tissues and an ideal candidate for both intrinsic and targeted biomarker-based imaging. It is hypothesized that these unparalleled imaging capabilities will allow observations of new classes of dynamic interactions at different time scales, from relatively slow varying inflammation-related molecular events to video rate visualization of neuronal activity in deep brain regions, otherwise invisible with other imaging methods.
Summary
The ability to visualize biological processes in living organisms continuously, instead of at discrete time points, holds a great promise for studies of functional and molecular events, disease progression and treatment monitoring. Optical spectrum is particularly attractive for biological interrogations as it can impart highly versatile contrast of cellular and sub-cellular function as well as employ highly specific contrast agents and markers not available for other modalities. However, technical limitations arising from intense light scattering in living tissues bound the main-stream of high resolution optical imaging applications to microscopic studies at shallow depths that do not allow the exploration of the full potential of novel classes of agents for volumetric imaging of entire organs, small animals or human tissues.
To overcome limitations of the current imaging techniques, this proposal aims to develop a novel high performance optoacoustic imaging technology and explore its groundbreaking potential for neuroimaging and monitoring of cardiovascular disease. I will undertake a substantial technological step that will bring optoacoustic imaging to a real time (video rate) high resolution performance level the like of which has not existed so far. The resulting technique will be able to image several millimeters to centimeters into living small animals and potentially humans, with both high spatial resolution and sensitivity, being independent of photon scattering. This will make it suitable for attaining high dynamic contrast in intact tissues and an ideal candidate for both intrinsic and targeted biomarker-based imaging. It is hypothesized that these unparalleled imaging capabilities will allow observations of new classes of dynamic interactions at different time scales, from relatively slow varying inflammation-related molecular events to video rate visualization of neuronal activity in deep brain regions, otherwise invisible with other imaging methods.
Max ERC Funding
1 452 650 €
Duration
Start date: 2010-10-01, End date: 2015-09-30
Project acronym EVOLVE
Project Extracellular Vesicle-Internalizing Receptors (EVIRs) for Cancer ImmunoGeneTherapy
Researcher (PI) Michele DE PALMA
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary We are witnessing transformative results in the clinical application of both cancer immunotherapies and gene transfer
technologies. Tumor vaccines are a specific modality of cancer immunotherapy. Similar to vaccination against pathogens, tumor vaccines are designed to elicit a specific immune response against cancer. They are based on the administration of inactivated cancer cells or tumor antigens, or the inoculation of antigen-presenting cells (APCs) previously exposed to tumor antigens. In spite of significant development and testing, tumor vaccines have largely delivered unsatisfactory clinical results. Indeed, while some patients show dramatic and durable cancer regressions, many do not respond, highlighting both the potential and the shortcomings of current vaccination strategies. Hence, identifying and abating the barriers to effective cancer vaccines is key to broadening their therapeutic reach. The goal of EVOLVE (EVirs to Optimize and Leverage Vaccines for cancer Eradication) is to propel the development of effective APC-based tumor vaccines using an innovative strategy that overcomes several key hurdles associated with available treatments. EVOLVE puts forward a novel APC engineering platform whereby chimeric receptors are used to both enable the specific and efficient uptake of cancer-derived extracellular vesicles (EVs) into APCs, and to promote the cross-presentation of EV-associated tumor antigens for stimulating anti-tumor immunity. EVOLVE also envisions a combination of ancillary ‘outside of the box’ interventions, primarily based on further APC engineering combined with innovative pre-conditioning of the tumor microenvironment, to facilitate the deployment of effective APC-driven, T-cellmediated anti-tumor immunity. Further to preclinical trials in mouse models of breast cancer and melanoma, our APC platform will be used to prospectively identify novel human melanoma antigens and reactive T cell clones for broader immunotherapy applications.
Summary
We are witnessing transformative results in the clinical application of both cancer immunotherapies and gene transfer
technologies. Tumor vaccines are a specific modality of cancer immunotherapy. Similar to vaccination against pathogens, tumor vaccines are designed to elicit a specific immune response against cancer. They are based on the administration of inactivated cancer cells or tumor antigens, or the inoculation of antigen-presenting cells (APCs) previously exposed to tumor antigens. In spite of significant development and testing, tumor vaccines have largely delivered unsatisfactory clinical results. Indeed, while some patients show dramatic and durable cancer regressions, many do not respond, highlighting both the potential and the shortcomings of current vaccination strategies. Hence, identifying and abating the barriers to effective cancer vaccines is key to broadening their therapeutic reach. The goal of EVOLVE (EVirs to Optimize and Leverage Vaccines for cancer Eradication) is to propel the development of effective APC-based tumor vaccines using an innovative strategy that overcomes several key hurdles associated with available treatments. EVOLVE puts forward a novel APC engineering platform whereby chimeric receptors are used to both enable the specific and efficient uptake of cancer-derived extracellular vesicles (EVs) into APCs, and to promote the cross-presentation of EV-associated tumor antigens for stimulating anti-tumor immunity. EVOLVE also envisions a combination of ancillary ‘outside of the box’ interventions, primarily based on further APC engineering combined with innovative pre-conditioning of the tumor microenvironment, to facilitate the deployment of effective APC-driven, T-cellmediated anti-tumor immunity. Further to preclinical trials in mouse models of breast cancer and melanoma, our APC platform will be used to prospectively identify novel human melanoma antigens and reactive T cell clones for broader immunotherapy applications.
Max ERC Funding
1 958 919 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
Project acronym GvHDCure
Project Understanding the dynamics of the immune system to cure graft-versus-host disease (GvHD).
Researcher (PI) Robert Franz Karl Zeiser
Host Institution (HI) UNIVERSITAETSKLINIKUM FREIBURG
Call Details Consolidator Grant (CoG), LS7, ERC-2015-CoG
Summary Acute graft-versus-host disease (GvHD) is the leading cause of the high mortality of patients having undergone allogeneic hematopoietic cell transplantation. A key event in the pathogenesis of GvHD is the injury and loss of epithelial cells in the intestinal tract. The overall goal of GvHDCure is to identify the pathophysiological mechanisms that initiate (1), propagate (2) and maintain (3) GvHD.
(1) We found that one of the earliest events during GvHD initiation is infiltration of the intestines by neutrophils. By using transgenic neutrophil cell lines carrying selective gene defects, we will systematically evaluate molecules in neutrophils that are critical for their sensing and effector function during GvHD in combination with novel imaging methods to track bacterial translocation. (2) The molecular programs propagating inflammation-induced epithelial apoptosis, endoplasmic reticulum stress and the sensing of DAMPs in GvHD are not understood. We will isolate enterocytes from GvHD mice to develop a precise quantitative genomic and micro RNA (miR) fingerprint of their death. The connection between ER stress and enterocyte death will be validated in intestinal organoid culture systems and in vivo in an XBP-1 mRNA splicing reporter mouse. In addition, we will make use of our human tissue bank, allowing the efficient genetic screening and verification of regulatory molecular networks in the cells from GvHD patients. (3) Maintenance of GvHD relies on continuous immune cell activation. Based on our miR array and phospho-proteomics data set, we will selectively analyze the role of several miRs and kinases in neutrophils, dendritic cells, T cells and enterocytes for GvHD maintenance by using multiple Cre-lox mice and kinase inhibitors to manipulate GvHD. Via a combination of murine and human studies GvHDCure aims to directly develop individualized therapeutic strategies to interfere with GvHD at multiple levels to make allo-HCT more safe for patients with blood cancer.
Summary
Acute graft-versus-host disease (GvHD) is the leading cause of the high mortality of patients having undergone allogeneic hematopoietic cell transplantation. A key event in the pathogenesis of GvHD is the injury and loss of epithelial cells in the intestinal tract. The overall goal of GvHDCure is to identify the pathophysiological mechanisms that initiate (1), propagate (2) and maintain (3) GvHD.
(1) We found that one of the earliest events during GvHD initiation is infiltration of the intestines by neutrophils. By using transgenic neutrophil cell lines carrying selective gene defects, we will systematically evaluate molecules in neutrophils that are critical for their sensing and effector function during GvHD in combination with novel imaging methods to track bacterial translocation. (2) The molecular programs propagating inflammation-induced epithelial apoptosis, endoplasmic reticulum stress and the sensing of DAMPs in GvHD are not understood. We will isolate enterocytes from GvHD mice to develop a precise quantitative genomic and micro RNA (miR) fingerprint of their death. The connection between ER stress and enterocyte death will be validated in intestinal organoid culture systems and in vivo in an XBP-1 mRNA splicing reporter mouse. In addition, we will make use of our human tissue bank, allowing the efficient genetic screening and verification of regulatory molecular networks in the cells from GvHD patients. (3) Maintenance of GvHD relies on continuous immune cell activation. Based on our miR array and phospho-proteomics data set, we will selectively analyze the role of several miRs and kinases in neutrophils, dendritic cells, T cells and enterocytes for GvHD maintenance by using multiple Cre-lox mice and kinase inhibitors to manipulate GvHD. Via a combination of murine and human studies GvHDCure aims to directly develop individualized therapeutic strategies to interfere with GvHD at multiple levels to make allo-HCT more safe for patients with blood cancer.
Max ERC Funding
1 987 500 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym HealthierWomen
Project A woman's reproductive experience: Long-term implications for chronic disease and death
Researcher (PI) Rolv SKJAERVEN
Host Institution (HI) UNIVERSITETET I BERGEN
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary Pregnancy complications such as preeclampsia and preterm birth are known to affect infant health, but their influence on mothers’ long-term health is not well understood. Most previous studies are seriously limited by their reliance on information from the first pregnancy. Often they lack the data to study women’s complete reproductive histories. Without a complete reproductive history, the relationship between pregnancy complications and women’s long-term health cannot be reliably studied. The Medical Birth Registry of Norway, covering all births from 1967-, includes information on more than 3 million births and 1.5 million sibships. Linking this to population based death and cancer registries provides a worldwide unique source of population-based data which can be analysed to identify heterogeneities in risk by lifetime parity and the cumulative experience of pregnancy complications. Having worked in this field of research for many years, I see many erroneous conclusions in studies based on insufficient data. For instance, both after preeclampsia and after a stillbirth, the high risk of heart disease observed in one-child mothers is strongly attenuated in women with subsequent pregnancies. I will study different patterns of pregnancy complications that occur alone or in combination across pregnancies, and analyse their associations with cause specific maternal mortality. Using this unique methodology, I will challenge the idea that placental dysfunction is the origin of preeclampsia and test the hypothesis that pregnancy complications may cause direct long-term effects on maternal health. The findings of this research have the potential to advance our understanding of how pregnancy complications affect the long-term maternal health and help to develop more effective chronic disease prevention strategies.
Summary
Pregnancy complications such as preeclampsia and preterm birth are known to affect infant health, but their influence on mothers’ long-term health is not well understood. Most previous studies are seriously limited by their reliance on information from the first pregnancy. Often they lack the data to study women’s complete reproductive histories. Without a complete reproductive history, the relationship between pregnancy complications and women’s long-term health cannot be reliably studied. The Medical Birth Registry of Norway, covering all births from 1967-, includes information on more than 3 million births and 1.5 million sibships. Linking this to population based death and cancer registries provides a worldwide unique source of population-based data which can be analysed to identify heterogeneities in risk by lifetime parity and the cumulative experience of pregnancy complications. Having worked in this field of research for many years, I see many erroneous conclusions in studies based on insufficient data. For instance, both after preeclampsia and after a stillbirth, the high risk of heart disease observed in one-child mothers is strongly attenuated in women with subsequent pregnancies. I will study different patterns of pregnancy complications that occur alone or in combination across pregnancies, and analyse their associations with cause specific maternal mortality. Using this unique methodology, I will challenge the idea that placental dysfunction is the origin of preeclampsia and test the hypothesis that pregnancy complications may cause direct long-term effects on maternal health. The findings of this research have the potential to advance our understanding of how pregnancy complications affect the long-term maternal health and help to develop more effective chronic disease prevention strategies.
Max ERC Funding
2 500 000 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym HEALTHMPOWR
Project A New Paradigm for Public Health Surveillance: Unlocking the Potential of Data to Empower Women and Health Systems
Researcher (PI) Jahn Frederik Froen
Host Institution (HI) FOLKEHELSEINSTITUTTET
Call Details Consolidator Grant (CoG), LS7, ERC-2013-CoG
Summary Rationale: State of the art health registries, cornerstones of public health surveillance, have hardly capitalized on the information and communication technology revolution. Many continue to be static, fragmented, and passive data repositories disseminating outdated reports only to a closed loop of public health officials.
Aim: In a radical departure from traditional science, this proposal introduces a new paradigm for public health surveillance: Maximizing the potential of data by disseminating data-driven individualized real-time information directly to women and providers to empower self-care in pregnancy and better healthcare delivery.
Research question: Is routine, data-driven and automated feedback from a reproductive health registry (RHR) effective in improving health behaviour and quality of care?
Plan: Based on the roll-out of a RHR in the Palestinian West Bank, four stepped wedged cluster randomized controlled trials will be undertaken to investigate the comparative effectiveness of a series of feedback modules to women and care providers. Main outcomes include adherence to evidence-based guidelines for providers, and self-care and care seeking among women.
Impact: Coalescing with WHO/NIPH’s dissemination of the harmonized Reproductive Health Registries (hRHR) Initiative, the scientific horizons emerging from this proposal have potential for exceptional impact. Radically transforming public health surveillance by empowering women and health care providers with information can translate into better health care and behaviours thus saving lives.
Summary
Rationale: State of the art health registries, cornerstones of public health surveillance, have hardly capitalized on the information and communication technology revolution. Many continue to be static, fragmented, and passive data repositories disseminating outdated reports only to a closed loop of public health officials.
Aim: In a radical departure from traditional science, this proposal introduces a new paradigm for public health surveillance: Maximizing the potential of data by disseminating data-driven individualized real-time information directly to women and providers to empower self-care in pregnancy and better healthcare delivery.
Research question: Is routine, data-driven and automated feedback from a reproductive health registry (RHR) effective in improving health behaviour and quality of care?
Plan: Based on the roll-out of a RHR in the Palestinian West Bank, four stepped wedged cluster randomized controlled trials will be undertaken to investigate the comparative effectiveness of a series of feedback modules to women and care providers. Main outcomes include adherence to evidence-based guidelines for providers, and self-care and care seeking among women.
Impact: Coalescing with WHO/NIPH’s dissemination of the harmonized Reproductive Health Registries (hRHR) Initiative, the scientific horizons emerging from this proposal have potential for exceptional impact. Radically transforming public health surveillance by empowering women and health care providers with information can translate into better health care and behaviours thus saving lives.
Max ERC Funding
2 212 136 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
Project acronym HEPATOPANCREATIC
Project MECHANISMS UNDERLYING CELL FATE DECISION BETWEEN PANCREAS AND LIVER
Researcher (PI) Francesca M Spagnoli
Host Institution (HI) MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Call Details Starting Grant (StG), LS7, ERC-2009-StG
Summary Diabetes is a degenerative disease affecting millions of persons worldwide. A cure for diabetes depends on replacing the insulin-producing ²-cells in the pancreas that are destroyed by the disease. An attractive strategy to attain this goal is to convert liver adult cells of the same patient into pancreatic ²-cells. The liver and pancreas share many aspects of their early development and are specified in adjacent regions of the endoderm, possibly from a common bipotent progenitor cell. Therefore, conversion of liver to pancreas is conceivable and should imply only few steps backward to a common progenitor and little epigenetic changes. However, how pancreatic versus hepatic fate decision occurs during development is still poorly understood. The aim of this proposal is two fold: to perform lineage analysis, and to study developmental regulators of pancreatic versus hepatic fate decision. We will use new genetic tools, based on the GFP and photoconvertible Kaede fluorescent proteins, to address: i. if the liver and pancreas arise from a common bipotent progenitor cell; ii. to trace in vivo; and iii. molecularly profile the presumptive precursor cell and its descendants in the mouse embryo. Our previous studies have identified target genes of the GATA factors that might act as intrinsic developmental regulators of the pancreatic versus hepatic fate decision. Both intrinsic factors together with extrinsic regulators, such as BMP, will be studied. We will test their potential to promote lineage reprogramming of liver to pancreas using the mouse as well as mouse embryonic stem cells as model systems. Understanding how distinct cell types arise from common multipotent progenitor cells is a major quest in developmental biology. Our findings will elucidate the spatiotemporal mechanisms that control pancreas versus liver fate decision. In addition, they will provide the blueprint for lineage reprogramming of adult hepatic cells to pancreas in diabetes cell-therapy.
Summary
Diabetes is a degenerative disease affecting millions of persons worldwide. A cure for diabetes depends on replacing the insulin-producing ²-cells in the pancreas that are destroyed by the disease. An attractive strategy to attain this goal is to convert liver adult cells of the same patient into pancreatic ²-cells. The liver and pancreas share many aspects of their early development and are specified in adjacent regions of the endoderm, possibly from a common bipotent progenitor cell. Therefore, conversion of liver to pancreas is conceivable and should imply only few steps backward to a common progenitor and little epigenetic changes. However, how pancreatic versus hepatic fate decision occurs during development is still poorly understood. The aim of this proposal is two fold: to perform lineage analysis, and to study developmental regulators of pancreatic versus hepatic fate decision. We will use new genetic tools, based on the GFP and photoconvertible Kaede fluorescent proteins, to address: i. if the liver and pancreas arise from a common bipotent progenitor cell; ii. to trace in vivo; and iii. molecularly profile the presumptive precursor cell and its descendants in the mouse embryo. Our previous studies have identified target genes of the GATA factors that might act as intrinsic developmental regulators of the pancreatic versus hepatic fate decision. Both intrinsic factors together with extrinsic regulators, such as BMP, will be studied. We will test their potential to promote lineage reprogramming of liver to pancreas using the mouse as well as mouse embryonic stem cells as model systems. Understanding how distinct cell types arise from common multipotent progenitor cells is a major quest in developmental biology. Our findings will elucidate the spatiotemporal mechanisms that control pancreas versus liver fate decision. In addition, they will provide the blueprint for lineage reprogramming of adult hepatic cells to pancreas in diabetes cell-therapy.
Max ERC Funding
1 186 746 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym HERA
Project Host-environment interactions in the protection from asthma and allergies
Researcher (PI) Erika Von Mutius
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS7, ERC-2009-AdG
Summary Asthma and allergies are chronic conditions affecting billions of Europeans. These complex diseases are determined by interplay of genetic and environmental factors. Treatments can control symptoms, but cannot cure or prevent the diseases. I, and my team, have shown that children are strongly protected from asthma and allergies when growing up in a farming environment rich in microbial exposures: the prevalence of asthma and hay fever is reduced over 5 fold. We have shown that environmental exposure to microbial compounds is inversely related to asthma and allergies. We have isolated microbes from animal sheds which protect mice from allergic airway inflammation. My team is now at a critical point to move this work forward to the next step, which is to systematically identify the microbes and their immuno-stimulatory compounds that protect from asthma and allergies. We have key resources in hand. In previous population based studies large numbers of environmental samples from farm and non farm children with and without asthma and allergies have been stored in biobanks. Genome wide genotyping data have also been gathered. The HERA project aims at applying the latest innovative high throughput sequencing techniques to comprehensively characterize the microbial ecology of these environmental samples. New methods for assessing microbial immuno-stimulatory substances will be used. These innovations will allow the HERA team to identify distinct asthma and allergy protective microbial exposures taking each individual s genetic susceptibility into account. Once protective microbial exposures have been identified, the responsible substances can be isolated. These substances can be developed into novel and effective prevention strategies to combat the asthma and allergy epidemic.
Summary
Asthma and allergies are chronic conditions affecting billions of Europeans. These complex diseases are determined by interplay of genetic and environmental factors. Treatments can control symptoms, but cannot cure or prevent the diseases. I, and my team, have shown that children are strongly protected from asthma and allergies when growing up in a farming environment rich in microbial exposures: the prevalence of asthma and hay fever is reduced over 5 fold. We have shown that environmental exposure to microbial compounds is inversely related to asthma and allergies. We have isolated microbes from animal sheds which protect mice from allergic airway inflammation. My team is now at a critical point to move this work forward to the next step, which is to systematically identify the microbes and their immuno-stimulatory compounds that protect from asthma and allergies. We have key resources in hand. In previous population based studies large numbers of environmental samples from farm and non farm children with and without asthma and allergies have been stored in biobanks. Genome wide genotyping data have also been gathered. The HERA project aims at applying the latest innovative high throughput sequencing techniques to comprehensively characterize the microbial ecology of these environmental samples. New methods for assessing microbial immuno-stimulatory substances will be used. These innovations will allow the HERA team to identify distinct asthma and allergy protective microbial exposures taking each individual s genetic susceptibility into account. Once protective microbial exposures have been identified, the responsible substances can be isolated. These substances can be developed into novel and effective prevention strategies to combat the asthma and allergy epidemic.
Max ERC Funding
2 155 697 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym iAML-lncTARGET
Project Targeting the transcriptional landscape in infant AML
Researcher (PI) Jan-Henning Cornelius KLUSMANN
Host Institution (HI) MARTIN-LUTHER-UNIVERSITAET HALLE-WITTENBERG
Call Details Starting Grant (StG), LS7, ERC-2016-STG
Summary Infant acute myeloid leukemia (AML) has a dismal prognosis, with a high prevalence of unfavorable features and increased susceptibility to therapy-related toxicities, highlighting the need for innovative treatment approaches. Despite the discovery of an enormous number and diversity of transcriptional products arising from the previously presumed wastelands of the non-protein-coding genome, our knowledge of non-coding RNAs is far from being incorporated into standards of AML diagnosis and treatment. I hypothesize that the highly developmental stage- and cell-specific expression of long non-coding RNAs shapes a chromatin and transcriptional landscape in fetal hematopoietic stem cells that renders them permissive towards transformation. I predict this landscape to synergize with particular oncogenes that are otherwise not oncogenic in adult cells, by providing a fertile transcriptional background for establishing and maintaining oncogenic programs. Therefore, the non-coding transcriptome, inherited from the fetal cell of origin, may reflect a previously unrecognized Achilles heel of infant AML, which I will identify with my expertise to understand and edit the AML genome and transcriptome.
I will apply recent breakthroughs from various research areas to i) create a comprehensive transcriptomic atlas of infant AML and fetal stem cells, ii) define aberrant or fetal stage-specific non-coding RNAs that drive leukemia progression, and iii) resolve their features to probe the oncogenic interactome. After iv) establishing a biobank of patient-derived xenografts, I will v) evaluate preclinical RNA-centered therapeutic interventions to overcome current obstacles in the treatment of infant AML. Targeting the vulnerable fetal stage-specific background of infant AML inherited from the cell of origin may set a paradigm shift for cancer treatment, by focusing on the permissive basis required by the oncogene for inducing and sustaining cancer, rather than on the oncogene itself.
Summary
Infant acute myeloid leukemia (AML) has a dismal prognosis, with a high prevalence of unfavorable features and increased susceptibility to therapy-related toxicities, highlighting the need for innovative treatment approaches. Despite the discovery of an enormous number and diversity of transcriptional products arising from the previously presumed wastelands of the non-protein-coding genome, our knowledge of non-coding RNAs is far from being incorporated into standards of AML diagnosis and treatment. I hypothesize that the highly developmental stage- and cell-specific expression of long non-coding RNAs shapes a chromatin and transcriptional landscape in fetal hematopoietic stem cells that renders them permissive towards transformation. I predict this landscape to synergize with particular oncogenes that are otherwise not oncogenic in adult cells, by providing a fertile transcriptional background for establishing and maintaining oncogenic programs. Therefore, the non-coding transcriptome, inherited from the fetal cell of origin, may reflect a previously unrecognized Achilles heel of infant AML, which I will identify with my expertise to understand and edit the AML genome and transcriptome.
I will apply recent breakthroughs from various research areas to i) create a comprehensive transcriptomic atlas of infant AML and fetal stem cells, ii) define aberrant or fetal stage-specific non-coding RNAs that drive leukemia progression, and iii) resolve their features to probe the oncogenic interactome. After iv) establishing a biobank of patient-derived xenografts, I will v) evaluate preclinical RNA-centered therapeutic interventions to overcome current obstacles in the treatment of infant AML. Targeting the vulnerable fetal stage-specific background of infant AML inherited from the cell of origin may set a paradigm shift for cancer treatment, by focusing on the permissive basis required by the oncogene for inducing and sustaining cancer, rather than on the oncogene itself.
Max ERC Funding
1 499 750 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym iBack
Project Individualized treatment planning in chronic back pain patients by advanced imaging and multi-parametric biomechanical models
Researcher (PI) Jan Stefan Bauer
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Starting Grant (StG), LS7, ERC-2014-STG
Summary Chronic back pain is a major burden and source of disability worldwide. It is primarily attributed to biomechanical factors. In elderly patients, osteoporosis complicates the biomechanical scenario. Surgery is often required to treat instability-related pain and to restore the balance of the spine. However, when and how to perform surgery remains a highly subjective decision based on the surgeon’s experience, with 2/3 of patients experiencing prolonged pain.
We recently established objective, image-based criteria for surgery outcome prediction. As an example, we were able to develop tools for routine density and fracture assessment and demonstrate that screw loosening occurs in >85% of patients with bone mineral density <92 mg/ccm. This directly influences the surgical approach in all spine surgery patients at our institution. Additionally, we improved the prediction of bone strength by advanced image post processing such as scaling indices, finite element and finite cell models.
The high-level objective of iBack is to individualize therapy planning in back pain patients. We will improve in-vivo imaging and image analysis to compute individualized biomechanical models that reveal the underlying pathophysiologic process and allow personalized treatment planning and outcome prediction after spine surgery or conservative treatment.
The main objectives of iBack are: (1) improving computed tomography (CT) and magnetic resonance imaging (MRI) of the spine; (2) combining sagittal balance radiographs, CT and MRI of the spine in one biomechanical multi-body simulation (MBS); (3) creating a statistical model that includes both clinical and biomechanical information to reveal interactions between the two and to predict individual treatment success probability.
The results of iBack will help to better understand instability-related pain and develop personalized surgical strategies which will have major impacts on patients.
Summary
Chronic back pain is a major burden and source of disability worldwide. It is primarily attributed to biomechanical factors. In elderly patients, osteoporosis complicates the biomechanical scenario. Surgery is often required to treat instability-related pain and to restore the balance of the spine. However, when and how to perform surgery remains a highly subjective decision based on the surgeon’s experience, with 2/3 of patients experiencing prolonged pain.
We recently established objective, image-based criteria for surgery outcome prediction. As an example, we were able to develop tools for routine density and fracture assessment and demonstrate that screw loosening occurs in >85% of patients with bone mineral density <92 mg/ccm. This directly influences the surgical approach in all spine surgery patients at our institution. Additionally, we improved the prediction of bone strength by advanced image post processing such as scaling indices, finite element and finite cell models.
The high-level objective of iBack is to individualize therapy planning in back pain patients. We will improve in-vivo imaging and image analysis to compute individualized biomechanical models that reveal the underlying pathophysiologic process and allow personalized treatment planning and outcome prediction after spine surgery or conservative treatment.
The main objectives of iBack are: (1) improving computed tomography (CT) and magnetic resonance imaging (MRI) of the spine; (2) combining sagittal balance radiographs, CT and MRI of the spine in one biomechanical multi-body simulation (MBS); (3) creating a statistical model that includes both clinical and biomechanical information to reveal interactions between the two and to predict individual treatment success probability.
The results of iBack will help to better understand instability-related pain and develop personalized surgical strategies which will have major impacts on patients.
Max ERC Funding
1 493 492 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
Project acronym iHEAR
Project Gene therapy of inherited and acquired hearing loss
Researcher (PI) Axel Rainer Schambach
Host Institution (HI) MEDIZINISCHE HOCHSCHULE HANNOVER
Call Details Consolidator Grant (CoG), LS7, ERC-2018-COG
Summary To address the substantial financial and social burden caused by hearing loss in 360 million people world-wide, I aim to improve hearing via gene therapy to correct inherited and protect from acquired hearing loss. In vitro experiments will establish the best vector configurations for transfer of therapeutic genes and miRNAs into inner ear hair cells (HC) and spiral ganglion neurons (SGN). The efficiency of the best-performing vector designs will then be explored in vivo using fluorescent marker proteins. Cell-type specific and inducible promoters as well as receptor-targeted vectors will be employed as a safety measure and to ensure transgene expression in HC and SGN target cells. Once efficient transduction of appropriate target cells and proper expression of therapeutic proteins are demonstrated, I will perform proof-of-concept studies in hearing loss models, incl. established mouse models, to correct (WP1) or protect (WP2) from impaired hearing. To ensure translatability of these findings, I will generate human induced pluripotent stem cells (iPSC) from patients with hearing loss (WP3), so that I can test optimized constructs in human otic cells. Moreover, I have access to a collection of well-characterized samples from over 600 hearing loss patients, including children with congenital hearing loss in whom many novel monogenetic alterations were identified. These resources provide the unique opportunity to generate a novel toolbox for the treatment of hearing loss. In addition to lentiviral and adeno-associated viral (AAV) vector delivery of corrective or protective genes to treat hearing loss, I will apply state-of-the-art genome editing tools to model and correct mutations causative for hearing loss in cell lines, primary cells from murine models, human patients and patient-derived iPSC. This work will contribute to development of clinically translatable approaches for precision medicine strategies to improve hearing loss treatment.
Summary
To address the substantial financial and social burden caused by hearing loss in 360 million people world-wide, I aim to improve hearing via gene therapy to correct inherited and protect from acquired hearing loss. In vitro experiments will establish the best vector configurations for transfer of therapeutic genes and miRNAs into inner ear hair cells (HC) and spiral ganglion neurons (SGN). The efficiency of the best-performing vector designs will then be explored in vivo using fluorescent marker proteins. Cell-type specific and inducible promoters as well as receptor-targeted vectors will be employed as a safety measure and to ensure transgene expression in HC and SGN target cells. Once efficient transduction of appropriate target cells and proper expression of therapeutic proteins are demonstrated, I will perform proof-of-concept studies in hearing loss models, incl. established mouse models, to correct (WP1) or protect (WP2) from impaired hearing. To ensure translatability of these findings, I will generate human induced pluripotent stem cells (iPSC) from patients with hearing loss (WP3), so that I can test optimized constructs in human otic cells. Moreover, I have access to a collection of well-characterized samples from over 600 hearing loss patients, including children with congenital hearing loss in whom many novel monogenetic alterations were identified. These resources provide the unique opportunity to generate a novel toolbox for the treatment of hearing loss. In addition to lentiviral and adeno-associated viral (AAV) vector delivery of corrective or protective genes to treat hearing loss, I will apply state-of-the-art genome editing tools to model and correct mutations causative for hearing loss in cell lines, primary cells from murine models, human patients and patient-derived iPSC. This work will contribute to development of clinically translatable approaches for precision medicine strategies to improve hearing loss treatment.
Max ERC Funding
1 999 500 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym ImageLink
Project Multiparametric tumor imaging and beyond: Towards understanding in vivo signals
Researcher (PI) Bernd Jürgen Pichler
Host Institution (HI) EBERHARD KARLS UNIVERSITAET TUEBINGEN
Call Details Advanced Grant (AdG), LS7, ERC-2012-ADG_20120314
Summary Non-invasive preclinical and clinical imaging is a powerful tool and has a huge potential, specifically in the realm of oncology. Recently, our laboratory developed a novel multimodality imaging system, which combines positron emission tomography (PET) and magnetic resonance imaging (MRI), yielding temporally and spatially matched data. However, the molecular PET and functional MRI signals are very complex and are often not fully understood. Thus, we will cross-validate the complementary PET/MRI information with proteomics and metabolomics data to gain a better understanding of the in vivo image data and yield finally an accurate holistic tumor profile. The cross-validation will be supported by image-guided accurately dissected tumor substructures. Tumor metabolism, receptor status, hypoxia, perfusion, apoptosis and angiogenesis will be investigated by established PET tracers. In the same imaging session, functional parameters of the tumor, such as perfusion, oxygenation and morphology will be assessed by MRI. Beyond this, novel imaging ligands for senescence, tumor stroma, and fatty acid synthase, which have been recently recognized as emerging key-players in tumor progression and therapy resistance, will be developed. The individual in vivo and in vitro parameters will be fed into a data mining utilizing a computer learning approach with regression and classification methods to detect common patterns and the related pharmacokinetics behind the in vivo imaging parameters. Analysis of the dynamic PET data will be performed by compartment analysis and kinetic modelling. Overall aim is to gain a better understanding of imaging data, provide an accurate holistic in vivo tumor profile to support prognostic parameters for tumor progression and therapy response. Finally, the revealed information will lead to a more accurate selection of imaging biomarkers for diagnosis and therapy control and will provide input for new strategies in tumor-specific tracer development.
Summary
Non-invasive preclinical and clinical imaging is a powerful tool and has a huge potential, specifically in the realm of oncology. Recently, our laboratory developed a novel multimodality imaging system, which combines positron emission tomography (PET) and magnetic resonance imaging (MRI), yielding temporally and spatially matched data. However, the molecular PET and functional MRI signals are very complex and are often not fully understood. Thus, we will cross-validate the complementary PET/MRI information with proteomics and metabolomics data to gain a better understanding of the in vivo image data and yield finally an accurate holistic tumor profile. The cross-validation will be supported by image-guided accurately dissected tumor substructures. Tumor metabolism, receptor status, hypoxia, perfusion, apoptosis and angiogenesis will be investigated by established PET tracers. In the same imaging session, functional parameters of the tumor, such as perfusion, oxygenation and morphology will be assessed by MRI. Beyond this, novel imaging ligands for senescence, tumor stroma, and fatty acid synthase, which have been recently recognized as emerging key-players in tumor progression and therapy resistance, will be developed. The individual in vivo and in vitro parameters will be fed into a data mining utilizing a computer learning approach with regression and classification methods to detect common patterns and the related pharmacokinetics behind the in vivo imaging parameters. Analysis of the dynamic PET data will be performed by compartment analysis and kinetic modelling. Overall aim is to gain a better understanding of imaging data, provide an accurate holistic in vivo tumor profile to support prognostic parameters for tumor progression and therapy response. Finally, the revealed information will lead to a more accurate selection of imaging biomarkers for diagnosis and therapy control and will provide input for new strategies in tumor-specific tracer development.
Max ERC Funding
2 494 800 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
Project acronym IMCCA
Project Innovative Modelling to Optimise Control of Childhood Anaemia across Africa
Researcher (PI) Penelope Vounatsou
Host Institution (HI) SCHWEIZERISCHES TROPEN- UND PUBLIC HEALTH-INSTITUT
Call Details Advanced Grant (AdG), LS7, ERC-2012-ADG_20120314
Summary "Anaemia affects two-third of all preschool-aged children in Africa. Malnutrition, malaria and helminth infections are among the main factors contributing to anaemia in this age group, however their relative contribution across the continent is not well understood. Spatially explicit estimates of anaemia risk are important measures of child morbidity and mortality.
The goal of the project is to develop Bayesian geostatistical methodology for very large, non-stationary data and employ it to (i) determine the relative contribution of malaria, helminth infections and malnutrition on anaemia and severe anaemia burden among pre-school children; (ii) obtain spatially explicit estimates of the risk of anaemia, severe anaemia and number of affected children; (iii) characterize co-endemicity patterns of anaemia, malaria, helminth infection and malnutrition; and (iv) quantify the contribution of severe anaemia to child mortality.
This research will contribute novel statistical methodologies in (i) spatial analysis of very large non-stationary geostatistical data, (ii) variable selection within a non-stationary model for very large geostatistical data, (iii) modelling disease co-endemicity from spatially misaligned surveys arising from independent regression models and (iv) meta-analyses of heterogeneous large spatial data by coupling geostatistical with mathematical transmission models.
Applications of geostatistical methodology will help optimising interventions to combat anaemia by generating (i) the first anaemia risk map and number of affected preschool children across Africa which will guide efficient allocation of nutrient supplements and fortified foods; (ii) anaemia co-endemicity maps and estimates of the relative contribution of anaemia risk factors to design integrated interventions based on local conditions; and (ii) estimates of the anaemia-related mortality across Africa."
Summary
"Anaemia affects two-third of all preschool-aged children in Africa. Malnutrition, malaria and helminth infections are among the main factors contributing to anaemia in this age group, however their relative contribution across the continent is not well understood. Spatially explicit estimates of anaemia risk are important measures of child morbidity and mortality.
The goal of the project is to develop Bayesian geostatistical methodology for very large, non-stationary data and employ it to (i) determine the relative contribution of malaria, helminth infections and malnutrition on anaemia and severe anaemia burden among pre-school children; (ii) obtain spatially explicit estimates of the risk of anaemia, severe anaemia and number of affected children; (iii) characterize co-endemicity patterns of anaemia, malaria, helminth infection and malnutrition; and (iv) quantify the contribution of severe anaemia to child mortality.
This research will contribute novel statistical methodologies in (i) spatial analysis of very large non-stationary geostatistical data, (ii) variable selection within a non-stationary model for very large geostatistical data, (iii) modelling disease co-endemicity from spatially misaligned surveys arising from independent regression models and (iv) meta-analyses of heterogeneous large spatial data by coupling geostatistical with mathematical transmission models.
Applications of geostatistical methodology will help optimising interventions to combat anaemia by generating (i) the first anaemia risk map and number of affected preschool children across Africa which will guide efficient allocation of nutrient supplements and fortified foods; (ii) anaemia co-endemicity maps and estimates of the relative contribution of anaemia risk factors to design integrated interventions based on local conditions; and (ii) estimates of the anaemia-related mortality across Africa."
Max ERC Funding
2 494 800 €
Duration
Start date: 2013-10-01, End date: 2018-09-30
Project acronym IMCIS
Project Individualised medicine in chronic inflammatory skin diseases
Researcher (PI) Kilian Georg Eyerich
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary More than 100 million EU citizens suffer from chronic inflammatory skin diseases such as psoriasis and atopic eczema (AE). The diseases imply a devastating life quality similar to that of cancer, and cause direct socio-economic costs in the magnitude of 100 billion Euro each year in the EU. Despite all efforts, psoriasis and AE remain undertreated and the concept of individualised (also called precision) medicine could not be established in the field. Consequently, intensified research is demanded by organisations such as the WHO. Unmet medical needs are 1) a diagnostic gap, 2) lack of prediction possibilities to define the optimal therapy for an individual patient, and 3) a substantial number of non-responders to therapies. Reasons for these shortcomings are the heterogeneity of both psoriasis and AE and insufficient collaboration of clinical specialists, basic researchers, and bio-informaticians. This proposal aims at improving health care of inflammatory skin diseases by implying the concept of individualised medicine. The crucial step towards this goal is the ground-breaking idea to link deep clinical phenotyping to molecular signatures in lesional skin. Deep phenotyping means each patient is characterised by 86 clinical, histological, and laboratory attributes rather than the imprecise state-of-the art approach of rough diagnosing. Each attribute gets assigned to molecular events in lesional skin. Gene regions as well as key pathogenic molecules are identified in a novel gene network of inflamed skin, referred to as BRAIN (biological relevance assigned intelligent network). Candidate targets get validated using state-of-the-art cell culture systems and full skin models. This innovative and ambitious approach will substantially improve our knowledge of the pathogenesis and primary triggers of both psoriasis and AE, safe European health care systems direct costs in the magnitude of 10 billion Euro, and have a model character for complex diseases in general.
Summary
More than 100 million EU citizens suffer from chronic inflammatory skin diseases such as psoriasis and atopic eczema (AE). The diseases imply a devastating life quality similar to that of cancer, and cause direct socio-economic costs in the magnitude of 100 billion Euro each year in the EU. Despite all efforts, psoriasis and AE remain undertreated and the concept of individualised (also called precision) medicine could not be established in the field. Consequently, intensified research is demanded by organisations such as the WHO. Unmet medical needs are 1) a diagnostic gap, 2) lack of prediction possibilities to define the optimal therapy for an individual patient, and 3) a substantial number of non-responders to therapies. Reasons for these shortcomings are the heterogeneity of both psoriasis and AE and insufficient collaboration of clinical specialists, basic researchers, and bio-informaticians. This proposal aims at improving health care of inflammatory skin diseases by implying the concept of individualised medicine. The crucial step towards this goal is the ground-breaking idea to link deep clinical phenotyping to molecular signatures in lesional skin. Deep phenotyping means each patient is characterised by 86 clinical, histological, and laboratory attributes rather than the imprecise state-of-the art approach of rough diagnosing. Each attribute gets assigned to molecular events in lesional skin. Gene regions as well as key pathogenic molecules are identified in a novel gene network of inflamed skin, referred to as BRAIN (biological relevance assigned intelligent network). Candidate targets get validated using state-of-the-art cell culture systems and full skin models. This innovative and ambitious approach will substantially improve our knowledge of the pathogenesis and primary triggers of both psoriasis and AE, safe European health care systems direct costs in the magnitude of 10 billion Euro, and have a model character for complex diseases in general.
Max ERC Funding
1 495 906 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym ImPRESS
Project Imaging Perfusion Restrictions from Extracellular Solid Stress
Researcher (PI) Kyrre Eeg Emblem
Host Institution (HI) OSLO UNIVERSITETSSYKEHUS HF
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary Even the perfect cancer drug must reach its target to have an effect. The ImPRESS project main objective is to develop a novel imaging paradigm coined Restricted Perfusion Imaging (RPI) to reveal - for the first time in humans - vascular restrictions in solid cancers caused by mechanical solid stress, and use RPI to demonstrate that alleviating this force will repair the cancerous microenvironment and improve therapeutic response. Delivery of anti-cancer drugs to the tumor is critically dependent on a functional vascular bed. Developing biomarkers that can measure how mechanical forces in a solid tumor impair perfusion and promotes therapy resistance is essential for treatment of disease.
The ImPRESS project is based on the following observations; (I) pre-clinical work suggests that therapies targeting the tumor microenvironment and extracellular matrix may enhance drug delivery by decompressing tumor vessels; (II) results from animal models may not be transferable because compressive forces in human tumors in vivo can be many times higher; and (III) there are no available imaging technologies for medical diagnostics of solid stress in human cancers. Using RPI, ImPRESS will conduct a comprehensive series of innovative studies in brain cancer patients to answer three key questions: (Q1) Can we image vascular restrictions in human cancers and map how the vasculature changes with tumor growth or treatment? (Q2) Can we use medical engineering to image solid stress in vivo? (Q3) Can RPI show that matrix-depleting drugs improve patient response to conventional chemo- and radiation therapy as well as new targeted therapies?
The ImPRESS project holds a unique position to answer these questions by our unrivaled experience with advanced imaging of cancer patients. With successful delivery, ImPRESS will have a direct impact on patient treatment and establish an imaging paradigm that will pave the way for new scientific knowledge on how to revitalize cancer therapies.
Summary
Even the perfect cancer drug must reach its target to have an effect. The ImPRESS project main objective is to develop a novel imaging paradigm coined Restricted Perfusion Imaging (RPI) to reveal - for the first time in humans - vascular restrictions in solid cancers caused by mechanical solid stress, and use RPI to demonstrate that alleviating this force will repair the cancerous microenvironment and improve therapeutic response. Delivery of anti-cancer drugs to the tumor is critically dependent on a functional vascular bed. Developing biomarkers that can measure how mechanical forces in a solid tumor impair perfusion and promotes therapy resistance is essential for treatment of disease.
The ImPRESS project is based on the following observations; (I) pre-clinical work suggests that therapies targeting the tumor microenvironment and extracellular matrix may enhance drug delivery by decompressing tumor vessels; (II) results from animal models may not be transferable because compressive forces in human tumors in vivo can be many times higher; and (III) there are no available imaging technologies for medical diagnostics of solid stress in human cancers. Using RPI, ImPRESS will conduct a comprehensive series of innovative studies in brain cancer patients to answer three key questions: (Q1) Can we image vascular restrictions in human cancers and map how the vasculature changes with tumor growth or treatment? (Q2) Can we use medical engineering to image solid stress in vivo? (Q3) Can RPI show that matrix-depleting drugs improve patient response to conventional chemo- and radiation therapy as well as new targeted therapies?
The ImPRESS project holds a unique position to answer these questions by our unrivaled experience with advanced imaging of cancer patients. With successful delivery, ImPRESS will have a direct impact on patient treatment and establish an imaging paradigm that will pave the way for new scientific knowledge on how to revitalize cancer therapies.
Max ERC Funding
1 499 638 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym INDIVUHEART
Project Individualized early risk assessment for heart diseases
Researcher (PI) Thomas Hans Eschenhagen
Host Institution (HI) UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Call Details Advanced Grant (AdG), LS7, ERC-2013-ADG
Summary Heart failure (HF) is the common end-stage of different medical conditions. It is the only growing cardiovascular disease and its prognosis remains worse than that of many malignancies. The lack of evidence-based treatment for patients with diastolic HF (HFpEF) exemplifies that the current “one for all” therapy has to be advanced by an individualized approach. Inherited cardiomyopathies can serve as paradigmatic examples of different HF pathogenesis. Both gain- and loss-of-function mutations of the same gene cause disease, calling for disease-specific agonism or antagonism of this gene´s function. However, mutations alone do not predict the severity of cardiomyopathies nor therapy, because their impact on cardiac myocyte function is modified by numerous factors, including the genetic context. Today, patient-specific cardiac myocytes can be evaluated by the induced pluripotent stem cell (hiPSC) technology. Yet, unfolding the true potential of this technology requires robust, quantitative, high content assays. Our recently developed method to generate 3D-engineered heart tissue (EHT) from hiPSC provide an automated, high content analysis of heart muscle function and the response to stressors in the dish. The aim of this project is to make the technology a clinically applicable test. Major steps are (i) in depths clinical phenotyping and genotyping of patients with cardiomyopathies or HFpEF, (ii) follow-up of the clinical course, (iii) generation of hiPSC lines (40 patients, 40 healthy controls), and (iv) quantitative assessment of hiPSC-EHT function under basal conditions and in response to pro-arrhythmic or cardio-active drugs and chronic afterload enhancement. The product of this study is an SOP-based assay with standard values for hiPSC-EHT function/stress responses from healthy volunteers and patients with different heart diseases. The project could change clinical practice and be a step towards individualized risk prediction and therapy of HF.
Summary
Heart failure (HF) is the common end-stage of different medical conditions. It is the only growing cardiovascular disease and its prognosis remains worse than that of many malignancies. The lack of evidence-based treatment for patients with diastolic HF (HFpEF) exemplifies that the current “one for all” therapy has to be advanced by an individualized approach. Inherited cardiomyopathies can serve as paradigmatic examples of different HF pathogenesis. Both gain- and loss-of-function mutations of the same gene cause disease, calling for disease-specific agonism or antagonism of this gene´s function. However, mutations alone do not predict the severity of cardiomyopathies nor therapy, because their impact on cardiac myocyte function is modified by numerous factors, including the genetic context. Today, patient-specific cardiac myocytes can be evaluated by the induced pluripotent stem cell (hiPSC) technology. Yet, unfolding the true potential of this technology requires robust, quantitative, high content assays. Our recently developed method to generate 3D-engineered heart tissue (EHT) from hiPSC provide an automated, high content analysis of heart muscle function and the response to stressors in the dish. The aim of this project is to make the technology a clinically applicable test. Major steps are (i) in depths clinical phenotyping and genotyping of patients with cardiomyopathies or HFpEF, (ii) follow-up of the clinical course, (iii) generation of hiPSC lines (40 patients, 40 healthy controls), and (iv) quantitative assessment of hiPSC-EHT function under basal conditions and in response to pro-arrhythmic or cardio-active drugs and chronic afterload enhancement. The product of this study is an SOP-based assay with standard values for hiPSC-EHT function/stress responses from healthy volunteers and patients with different heart diseases. The project could change clinical practice and be a step towards individualized risk prediction and therapy of HF.
Max ERC Funding
2 494 728 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym INJURMET
Project Impact of tissue injury induced by diagnostic biopsies and surgery on cancer metastasis
Researcher (PI) Klaus Pantel
Host Institution (HI) UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary Background: Blood-borne metastasis of malignant cells from the primary lesion to distant organs is the major cause of cancer-related death. Most cancer patients face tissue injury at initial diagnosis when tumor tissue is obtained by biopsies to secure the diagnosis of cancer and at primary surgery required to remove the primary tumor.
Objectives: We will evaluate whether tissue injury contributes to a significant blood-borne dissemination of viable tumor cells, which is one of the most under-investigated areas in cancer research. We will focus on the two most frequent malignancies in women (breast cancer) and men (prostate cancer) that occur in the in European Union with incidence rates of 139.5 and 139.0 cases per 100,000, respectively. The current project will study the extent of the release of tumor cells into the blood circulation after needle tissue biopsies and primary surgery, the characteristics of the released tumor cells and the contribution of this release to cancer progression. Moreover, we will assess therapeutic strategies to block extravasation of circulating tumor cells (CTCs) to distant sites. As experimental approach, we will apply novel technologies for capturing CTCs and for determining their molecular characteristics in cancer patients as well as experimental models that are able to determine the functional properties of CTCs.
Impact: The results will have an important impact on medical practice. If biopsies would contribute to tumor progression, it might be a strong driving force for the development of better imaging modalities or “liquid biopsy” assays of peripheral blood that can diagnose cancer through the detection of CTCs or tumor cell products such as circulating nucleic acids (DNA, microRNA), exosomes or tumor-educated platelets. Moreover, short-term pharmacologic inhibition of extravasation might be able to prevent the extravasation of injury-released CTCs and reduce the risk of metastasis.
Summary
Background: Blood-borne metastasis of malignant cells from the primary lesion to distant organs is the major cause of cancer-related death. Most cancer patients face tissue injury at initial diagnosis when tumor tissue is obtained by biopsies to secure the diagnosis of cancer and at primary surgery required to remove the primary tumor.
Objectives: We will evaluate whether tissue injury contributes to a significant blood-borne dissemination of viable tumor cells, which is one of the most under-investigated areas in cancer research. We will focus on the two most frequent malignancies in women (breast cancer) and men (prostate cancer) that occur in the in European Union with incidence rates of 139.5 and 139.0 cases per 100,000, respectively. The current project will study the extent of the release of tumor cells into the blood circulation after needle tissue biopsies and primary surgery, the characteristics of the released tumor cells and the contribution of this release to cancer progression. Moreover, we will assess therapeutic strategies to block extravasation of circulating tumor cells (CTCs) to distant sites. As experimental approach, we will apply novel technologies for capturing CTCs and for determining their molecular characteristics in cancer patients as well as experimental models that are able to determine the functional properties of CTCs.
Impact: The results will have an important impact on medical practice. If biopsies would contribute to tumor progression, it might be a strong driving force for the development of better imaging modalities or “liquid biopsy” assays of peripheral blood that can diagnose cancer through the detection of CTCs or tumor cell products such as circulating nucleic acids (DNA, microRNA), exosomes or tumor-educated platelets. Moreover, short-term pharmacologic inhibition of extravasation might be able to prevent the extravasation of injury-released CTCs and reduce the risk of metastasis.
Max ERC Funding
2 499 985 €
Duration
Start date: 2019-08-01, End date: 2024-07-31
Project acronym ISIS
Project Identification and targeting of somatic changes initiating sporadic cancers
Researcher (PI) Christoph Klein
Host Institution (HI) UNIVERSITAET REGENSBURG
Call Details Advanced Grant (AdG), LS7, ERC-2012-ADG_20120314
Summary Cancer drugs are extremely ineffective, generally because current therapies do not address cellular heterogeneity. While hypothesis-driven research and functional genomics identify ever more novel putative therapeutic targets, the scientific community lacks rationales to attack the cellular heterogeneity in cancer, to select among the targets the most promising, and to design combination therapies. In particular, these all fail to provide successful adjuvant therapy settings after curative resection of the primary tumour before the onset of manifest metastasis.
Here I propose a novel way to address cancer cell heterogeneity and to develop a rationale for the design of adjuvant therapies. The proposal rests upon the premises that (i) cancer initiation is causally associated with genetic changes, (ii) early, functionally relevant genetic changes -particularly involving DNA loss- have the highest probability to be shared among the progeny of a monoclonal, yet genetically unstable, cancer, and (iii) subsequent, cumulative genetic changes must either add to the fitness of the cell or at least be neutral to enable progression. The proposal is then built upon our observation that a subgroup of disseminated cancer cells (DCCs) displays normal karyotypes and DNA changes smaller than 10 Mb whilst primary tumours and more advanced DCCs harbour multiple additional chromosomal changes at the time of analysis. I suggest that although these karyotypically normal DCCs are the putative “loser cells” in cancer progression - since they are arrested in bone marrow - they are central to uncovering the early genetic changes of an individual cancer. With these cells we will identify for the first time the catalogue of initiating changes of sporadic cancers in a systematic way. We will then test the function of the early aberrations and perform functional viability screens to develop novel systemic therapies that target the Achilles’ heel of a given cancer: its shared critical alteration.
Summary
Cancer drugs are extremely ineffective, generally because current therapies do not address cellular heterogeneity. While hypothesis-driven research and functional genomics identify ever more novel putative therapeutic targets, the scientific community lacks rationales to attack the cellular heterogeneity in cancer, to select among the targets the most promising, and to design combination therapies. In particular, these all fail to provide successful adjuvant therapy settings after curative resection of the primary tumour before the onset of manifest metastasis.
Here I propose a novel way to address cancer cell heterogeneity and to develop a rationale for the design of adjuvant therapies. The proposal rests upon the premises that (i) cancer initiation is causally associated with genetic changes, (ii) early, functionally relevant genetic changes -particularly involving DNA loss- have the highest probability to be shared among the progeny of a monoclonal, yet genetically unstable, cancer, and (iii) subsequent, cumulative genetic changes must either add to the fitness of the cell or at least be neutral to enable progression. The proposal is then built upon our observation that a subgroup of disseminated cancer cells (DCCs) displays normal karyotypes and DNA changes smaller than 10 Mb whilst primary tumours and more advanced DCCs harbour multiple additional chromosomal changes at the time of analysis. I suggest that although these karyotypically normal DCCs are the putative “loser cells” in cancer progression - since they are arrested in bone marrow - they are central to uncovering the early genetic changes of an individual cancer. With these cells we will identify for the first time the catalogue of initiating changes of sporadic cancers in a systematic way. We will then test the function of the early aberrations and perform functional viability screens to develop novel systemic therapies that target the Achilles’ heel of a given cancer: its shared critical alteration.
Max ERC Funding
2 499 982 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym LASERHEARINGAIDS
Project Laser: driving force for a new generation of hearing aids
Researcher (PI) Gentiana Ioana Constanta Wenzel
Host Institution (HI) UNIVERSITAT DES SAARLANDES
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary This proposal presents an unconventional method for the stimulation of the outer and middle ear that may change the current concept of hearing aids. Photons of the visible light are known to activate the visual sensory cells through photoreceptors. However, when the so-called stress-confinement condition is fulfilled, laser light can induce an acoustic signal through an optoacoustic effect. We demonstrated previously that these light induced sound waves, the optoacoustic waves, can be used to activate the inner ear, the cochlea. Unexpectedly, we found that not just the inner ear but also the middle and outer ear are responsive to laser pulses. However, simple activation of the auditory system is not a sufficient therapy in hearing impaired people. A controlled frequency specific activation of the complete audible frequency spectrum is mandatory to make speech and complex sounds of daily life perceptible and intelligible. The overall objective of this project is to establish methods for frequency specific activation of the complete audible spectrum using monochrome laser pulses. The frequency modulation is a well known process in physics that has to be proven as valid for biological systems as well. Successfull development of parameters for frequency modulation and speech coding resulting will create / provide the basis for a novel non-contact stimulation method that will revolutionize the implantable and non-implantable hearing aids by replacing the speaker or the sound transducer (force mass transducer, the Bone Anchored Hearing Aid screw) with the non contact and focused laser pulses. We expect that the development of these novel stimulation-strategy and stimulation-devices will ameliorate patients’ quality of life by significantly improving their aided hearing and comfort using the hearing device as well as reducing medical health care expenses determined through device related complications.
Summary
This proposal presents an unconventional method for the stimulation of the outer and middle ear that may change the current concept of hearing aids. Photons of the visible light are known to activate the visual sensory cells through photoreceptors. However, when the so-called stress-confinement condition is fulfilled, laser light can induce an acoustic signal through an optoacoustic effect. We demonstrated previously that these light induced sound waves, the optoacoustic waves, can be used to activate the inner ear, the cochlea. Unexpectedly, we found that not just the inner ear but also the middle and outer ear are responsive to laser pulses. However, simple activation of the auditory system is not a sufficient therapy in hearing impaired people. A controlled frequency specific activation of the complete audible frequency spectrum is mandatory to make speech and complex sounds of daily life perceptible and intelligible. The overall objective of this project is to establish methods for frequency specific activation of the complete audible spectrum using monochrome laser pulses. The frequency modulation is a well known process in physics that has to be proven as valid for biological systems as well. Successfull development of parameters for frequency modulation and speech coding resulting will create / provide the basis for a novel non-contact stimulation method that will revolutionize the implantable and non-implantable hearing aids by replacing the speaker or the sound transducer (force mass transducer, the Bone Anchored Hearing Aid screw) with the non contact and focused laser pulses. We expect that the development of these novel stimulation-strategy and stimulation-devices will ameliorate patients’ quality of life by significantly improving their aided hearing and comfort using the hearing device as well as reducing medical health care expenses determined through device related complications.
Max ERC Funding
1 276 698 €
Duration
Start date: 2012-10-01, End date: 2018-05-31
Project acronym LeukaemiaTargeted
Project Selecting genetic lesions with essential function for patients' leukaemia in vivo as targets for precision medicine
Researcher (PI) Irmela Jeremias
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Call Details Consolidator Grant (CoG), LS7, ERC-2015-CoG
Summary In Europe, around two million individuals die from cancer each year. Cancer is a genetic disease and each patient's tumour contains several genetic lesions which are identified by next generation sequencing (NGS) and influence patient's outcome. A global current challenge lies in translating NGS data into benefit of cancer patients.
As attractive novel therapeutic concept, precision medicine addresses genetic lesions using targeted therapies. A large number of targeted drugs and compounds exist and are currently developed such as kinase inhibitors; unfortunately, numerous clinical trials on targeted therapies failed.
In order to better exploit NGS data, it is important to discriminate between genetic lesions that are required and maintain patients' tumours in vivo and others that do not – an impossible mission so far. My proposal aims at solving this key question.
Using acute leukaemia as model tumour disease, we propagate primary tumour cells from patients in immuno-deficient mice. We recently pioneered a worldwide unique technique which allows the distinct genetic manipulation of individual patients' tumour cells while they grow in vivo.
We will molecularly target tumour-specific genetic lesions one by one; if tumour load is reduced, the lesion fulfils an essential function; essential lesions represent attractive therapeutic targets. Using our cutting edge technology, we will identify genetic lesions with essential, tumour-relevant function
(i) in established tumour disease and
(ii) in the clinically challenging situations of minimal residual disease and relapse.
Our approach implements a new paradigm for target selection in oncology. Our work introduces molecular target validation as important step into the value chain of precision medicine which will tailor drug development by industry and academia. Our approach will improve patient care and the success rate of clinical trials for the benefit of patients suffering acute leukaemia and putatively other cancers.
Summary
In Europe, around two million individuals die from cancer each year. Cancer is a genetic disease and each patient's tumour contains several genetic lesions which are identified by next generation sequencing (NGS) and influence patient's outcome. A global current challenge lies in translating NGS data into benefit of cancer patients.
As attractive novel therapeutic concept, precision medicine addresses genetic lesions using targeted therapies. A large number of targeted drugs and compounds exist and are currently developed such as kinase inhibitors; unfortunately, numerous clinical trials on targeted therapies failed.
In order to better exploit NGS data, it is important to discriminate between genetic lesions that are required and maintain patients' tumours in vivo and others that do not – an impossible mission so far. My proposal aims at solving this key question.
Using acute leukaemia as model tumour disease, we propagate primary tumour cells from patients in immuno-deficient mice. We recently pioneered a worldwide unique technique which allows the distinct genetic manipulation of individual patients' tumour cells while they grow in vivo.
We will molecularly target tumour-specific genetic lesions one by one; if tumour load is reduced, the lesion fulfils an essential function; essential lesions represent attractive therapeutic targets. Using our cutting edge technology, we will identify genetic lesions with essential, tumour-relevant function
(i) in established tumour disease and
(ii) in the clinically challenging situations of minimal residual disease and relapse.
Our approach implements a new paradigm for target selection in oncology. Our work introduces molecular target validation as important step into the value chain of precision medicine which will tailor drug development by industry and academia. Our approach will improve patient care and the success rate of clinical trials for the benefit of patients suffering acute leukaemia and putatively other cancers.
Max ERC Funding
1 945 818 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym LightTouch
Project Feeling with Light – Development of a multimodal optofluidic platform for high-content blood cell analysis
Researcher (PI) Jochen Guck
Host Institution (HI) TECHNISCHE UNIVERSITAET DRESDEN
Call Details Starting Grant (StG), LS7, ERC-2011-StG_20101109
Summary The reliable characterization of heterogeneous cell populations is a central prerequisite in many areas of medicine, biology, and biotechnology. Conventional techniques used for this purpose are either high-throughput, such as fluorescence-activated cell sorting (FACS), but limited to a small number of parameters or high-content, such as slide-based imaging approaches, which require surface attachment and preclude cell sorting. It is the overall objective of this proposal to develop a multimodal, microfluidic, laser trap-assisted cell screening platform technology – µFLAX – for the contact-free manipulation and high-content screening of suspended cells with high-throughput. Our approach is especially designed for blood cells, which will be serially trapped from microfluidic flow with a dual-beam trap. In addition to the extraction of molecular information (similar to FACS), we also incorporate mechanical phenotyping as a powerful new functional cell marker. In addition to looking, we can feel for functional changes using optically induced forces. This will be further augmented by structural analysis using digital holographic microscopy, cell size analysis using an optical cell rotator, and biological stimulation by microfluidic delivery of biochemical agents. This combination will offer much higher sensitivity and specificity in determining functional states compared to currently available techniques. And since the cells are suspended they can be sorted and analyzed further, which will aid potential molecular target identification. Once developed, we will demonstrate the applicability of µFLAX for the investigation and diagnosis of inflammation and infection. Based on our track record in pioneering innovative physical solutions to biomedical problems we anticipate that through this project we will provide novel insight into system biological aspects of these disorders on the single-cell level, as well as novel diagnostic and therapeutic options.
Summary
The reliable characterization of heterogeneous cell populations is a central prerequisite in many areas of medicine, biology, and biotechnology. Conventional techniques used for this purpose are either high-throughput, such as fluorescence-activated cell sorting (FACS), but limited to a small number of parameters or high-content, such as slide-based imaging approaches, which require surface attachment and preclude cell sorting. It is the overall objective of this proposal to develop a multimodal, microfluidic, laser trap-assisted cell screening platform technology – µFLAX – for the contact-free manipulation and high-content screening of suspended cells with high-throughput. Our approach is especially designed for blood cells, which will be serially trapped from microfluidic flow with a dual-beam trap. In addition to the extraction of molecular information (similar to FACS), we also incorporate mechanical phenotyping as a powerful new functional cell marker. In addition to looking, we can feel for functional changes using optically induced forces. This will be further augmented by structural analysis using digital holographic microscopy, cell size analysis using an optical cell rotator, and biological stimulation by microfluidic delivery of biochemical agents. This combination will offer much higher sensitivity and specificity in determining functional states compared to currently available techniques. And since the cells are suspended they can be sorted and analyzed further, which will aid potential molecular target identification. Once developed, we will demonstrate the applicability of µFLAX for the investigation and diagnosis of inflammation and infection. Based on our track record in pioneering innovative physical solutions to biomedical problems we anticipate that through this project we will provide novel insight into system biological aspects of these disorders on the single-cell level, as well as novel diagnostic and therapeutic options.
Max ERC Funding
1 385 683 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym LiverFibrosisImaging
Project Quantitative Imaging of Liver Fibrosis and Fibrogenesis
Researcher (PI) Detlef Schuppan
Host Institution (HI) UNIVERSITAETSMEDIZIN DER JOHANNES GUTENBERG-UNIVERSITAET MAINZ
Call Details Advanced Grant (AdG), LS7, ERC-2011-ADG_20110310
Summary Chronic liver disease can progress to cirrhosis, with death due to liver failure and cancer. Cirrhosis prevalence in the EU is 0.5%-1%. However, development of therapies that prevent progression to cirrhosis is hampered by the lack of a sensitive, non-invasive method to quantify fibrosis or fibrosis progression (fibrogenesis). Liver biopsy 1) is risky, 2) shows high sampling variability, and 3) is too insensitive to assess fibrosis progression in clinical studies. Conventional radiological imaging, serum markers, and ultrasound- or MR-elastography do neither permit exact fibrosis nor any fibrogenesis measurement.
We plan to develop a clinically applicable methodology to quantitate fibrosis and fibrogenesis over the whole liver using imaging agents that target and thus quantify abundant fibrillar collagen or key cells that drive fibrogenesis (activated myofibroblasts and cholangiocytes). We demonstrated the feasibility of this approach using radiolabeled conjugates of high affinity that target integrin alphaVbeta6 and PDGFbeta receptor that are cell surface molecules of activated cholangiocytes and myofibroblasts. i.v. injection of the integrin conjugate allowed quantitative imaging of alphaVbeta6 expression and correlated with whole liver fibrogenesis. We intend to optimize nonpeptide and peptide ligands for integrin alphaVbeta6, PDGF beta receptor and fibrillar collagens using novel linkers and oligomerization, using PET-radioimaging with Ga-68, Sc-44 and F-18. The targeted imaging constructs will be validated in vivo using established rodent models with defined liver fibrosis and fibrogenesis, with and without antifibrotic drug therapy. Translation to phase I and II clinical studies is planned in years 4-5 of the project.
The technology will for the first time allow for 1. individual risk assessment of fibrosis progression, and 2. rapid testing of antifibrotic drugs and their combinations in small groups of individual patients.
Summary
Chronic liver disease can progress to cirrhosis, with death due to liver failure and cancer. Cirrhosis prevalence in the EU is 0.5%-1%. However, development of therapies that prevent progression to cirrhosis is hampered by the lack of a sensitive, non-invasive method to quantify fibrosis or fibrosis progression (fibrogenesis). Liver biopsy 1) is risky, 2) shows high sampling variability, and 3) is too insensitive to assess fibrosis progression in clinical studies. Conventional radiological imaging, serum markers, and ultrasound- or MR-elastography do neither permit exact fibrosis nor any fibrogenesis measurement.
We plan to develop a clinically applicable methodology to quantitate fibrosis and fibrogenesis over the whole liver using imaging agents that target and thus quantify abundant fibrillar collagen or key cells that drive fibrogenesis (activated myofibroblasts and cholangiocytes). We demonstrated the feasibility of this approach using radiolabeled conjugates of high affinity that target integrin alphaVbeta6 and PDGFbeta receptor that are cell surface molecules of activated cholangiocytes and myofibroblasts. i.v. injection of the integrin conjugate allowed quantitative imaging of alphaVbeta6 expression and correlated with whole liver fibrogenesis. We intend to optimize nonpeptide and peptide ligands for integrin alphaVbeta6, PDGF beta receptor and fibrillar collagens using novel linkers and oligomerization, using PET-radioimaging with Ga-68, Sc-44 and F-18. The targeted imaging constructs will be validated in vivo using established rodent models with defined liver fibrosis and fibrogenesis, with and without antifibrotic drug therapy. Translation to phase I and II clinical studies is planned in years 4-5 of the project.
The technology will for the first time allow for 1. individual risk assessment of fibrosis progression, and 2. rapid testing of antifibrotic drugs and their combinations in small groups of individual patients.
Max ERC Funding
2 454 604 €
Duration
Start date: 2012-08-01, End date: 2017-07-31
Project acronym META-GROWTH
Project Metabolic regulation of growth and body composition: key modulators of long-term health
Researcher (PI) Berthold Koletzko
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS7, ERC-2012-ADG_20120314
Summary Nutrient exposure during pregnancy and childhood strongly affects growth and induces persistent metabolic programming of lifelong health. Recent data show that obesity and related disorders are induced by both fast childhood weight gain, and by formula feeding that promotes higher weight gain than breastfeeding. Lower protein in infant formula at levels similar to breast milk normalizes early weight gain and reduces later obesity risk as much as 2.5fold. Optimizing growth through improved substrate supply is of major importance for health prevention, but information is lacking on key mediators, effects on body composition and mechanisms of action, e.g. epigenetic modification. We use innovative approaches to identify key substrates that may mediate growth and body composition in humans, e.g. branched chain amino acids, n-6 polyunsaturated fatty acids, and others, and their epigenetic effects. We employ novel methods for high throughput targeted metabolomic and lipidomic profiling, genome-wide DNA methylation analysis, and state of the art bioinformatics. These powerful tools are applied to five well designed prospective cohort studies covering critical time periods from pregnancy to puberty. All cohorts offer precise phenotyping incl. body composition and are already or will be established. Comparative analyses across studies and populations provide added scientific value. We will identify which metabolic signals induce rapid weight gain and body fat deposition throughout childhood. We aim at identifying susceptible age periods, nutrient effects on epigenetic DNA methylation, and whether early metabolic exposures induce persistent or fluid metabolomic and epigenetic changes over time. The results should provide answers to key questions on the regulation of growth, with major benefit for scientific understanding, opportunities for future research, promotion of public health, nutrition recommendations, and development of improved food products.
Summary
Nutrient exposure during pregnancy and childhood strongly affects growth and induces persistent metabolic programming of lifelong health. Recent data show that obesity and related disorders are induced by both fast childhood weight gain, and by formula feeding that promotes higher weight gain than breastfeeding. Lower protein in infant formula at levels similar to breast milk normalizes early weight gain and reduces later obesity risk as much as 2.5fold. Optimizing growth through improved substrate supply is of major importance for health prevention, but information is lacking on key mediators, effects on body composition and mechanisms of action, e.g. epigenetic modification. We use innovative approaches to identify key substrates that may mediate growth and body composition in humans, e.g. branched chain amino acids, n-6 polyunsaturated fatty acids, and others, and their epigenetic effects. We employ novel methods for high throughput targeted metabolomic and lipidomic profiling, genome-wide DNA methylation analysis, and state of the art bioinformatics. These powerful tools are applied to five well designed prospective cohort studies covering critical time periods from pregnancy to puberty. All cohorts offer precise phenotyping incl. body composition and are already or will be established. Comparative analyses across studies and populations provide added scientific value. We will identify which metabolic signals induce rapid weight gain and body fat deposition throughout childhood. We aim at identifying susceptible age periods, nutrient effects on epigenetic DNA methylation, and whether early metabolic exposures induce persistent or fluid metabolomic and epigenetic changes over time. The results should provide answers to key questions on the regulation of growth, with major benefit for scientific understanding, opportunities for future research, promotion of public health, nutrition recommendations, and development of improved food products.
Max ERC Funding
2 491 200 €
Duration
Start date: 2013-10-01, End date: 2018-09-30
Project acronym MicroAdiPSChip
Project Micro-Fat Tissue on Chip
Researcher (PI) Matthias MEIER
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Call Details Consolidator Grant (CoG), LS7, ERC-2017-COG
Summary Human fat tissue has evolved to serve as a major energy reserve. An imbalance between energy intake and expenditure leads to an expansion of adipose tissue. Maintenance of this energy imbalance over longer times leads to obesity and metabolic disorders such as type 2 diabetes, for which clinical cures are not yet available. Adipocytes are the main cell type within the adipose tissue and can be divided into white, beige, and brown subtypes. White adipocytes store and mobilize energy, whereas beige and brown adipocytes store and burn energy during cold exposure to generate heat. An attractive strategy to restore the energy imbalance and treat obesity is to activate or increase the number of beige adipocytes in white adipose tissue. The main research obstacles affecting our ability to induce beige adipocytes is our lack of laboratory test systems recapitulating the microenvironmental conditions of the adipose tissue. Therefore, this research project aims to develop adipose tissue models outside organisms in sizes of micrometers for studying the differentiation of human inducible pluripotent stem cells (hiPSCs) into mature adipocytes. For assembly of the micro-fat tissues, we combine microfluidic and bioprinting technologies. In particular, the integration of micro-fat tissue on microfluidic chip platforms will be exploited to dynamically control the chemical, cell architectural, and mechanical microenvironment of hiPSCs incorporated in the micro-fat tissue. With novel single-cell-resolution in situ detection systems, we will aim to reveal, which microenvironmental stem cell niche factors are required to differentiate hiPSCs into metabolically active beige adipocytes. The acquired experimental data will help to mechanistically understand the role of natural stem cell niches, determine how to simulate them under laboratory conditions and finally provide patient-specific, clinically relevant information for developing new cell-based treatments for obesity.
Summary
Human fat tissue has evolved to serve as a major energy reserve. An imbalance between energy intake and expenditure leads to an expansion of adipose tissue. Maintenance of this energy imbalance over longer times leads to obesity and metabolic disorders such as type 2 diabetes, for which clinical cures are not yet available. Adipocytes are the main cell type within the adipose tissue and can be divided into white, beige, and brown subtypes. White adipocytes store and mobilize energy, whereas beige and brown adipocytes store and burn energy during cold exposure to generate heat. An attractive strategy to restore the energy imbalance and treat obesity is to activate or increase the number of beige adipocytes in white adipose tissue. The main research obstacles affecting our ability to induce beige adipocytes is our lack of laboratory test systems recapitulating the microenvironmental conditions of the adipose tissue. Therefore, this research project aims to develop adipose tissue models outside organisms in sizes of micrometers for studying the differentiation of human inducible pluripotent stem cells (hiPSCs) into mature adipocytes. For assembly of the micro-fat tissues, we combine microfluidic and bioprinting technologies. In particular, the integration of micro-fat tissue on microfluidic chip platforms will be exploited to dynamically control the chemical, cell architectural, and mechanical microenvironment of hiPSCs incorporated in the micro-fat tissue. With novel single-cell-resolution in situ detection systems, we will aim to reveal, which microenvironmental stem cell niche factors are required to differentiate hiPSCs into metabolically active beige adipocytes. The acquired experimental data will help to mechanistically understand the role of natural stem cell niches, determine how to simulate them under laboratory conditions and finally provide patient-specific, clinically relevant information for developing new cell-based treatments for obesity.
Max ERC Funding
1 775 000 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym MicroRepro
Project Medical microbots to support new assisted reproduction techniques
Researcher (PI) Oliver G. Schmidt
Host Institution (HI) LEIBNIZ-INSTITUT FUER FESTKOERPER- UND WERKSTOFFFORSCHUNG DRESDEN E.V.
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary Infertility is a health issue with sociological and psychological implications that affects approximately 50 million couples worldwide and therefore receives global attention. Among fertility issues, male infertility is diagnosed in about 40% of all cases and the major causes are poor motility of spermatozoa (asthenospermia), low sperm count (oligospermia), abnormal sperm morphology (teratospermia) and/or combinations of these, leading to their inability to fertilize an oocyte. Such problems have been mainly addressed by artificial insemination (AI) and in vitro fertilization (IVF). AI involves introducing sperms into a woman’s uterus with a medical instrument, but its applicability is limited and its success rate is below 30%. In contrast, IVF and intracytoplasmic sperm injection can be more effective but implicate more invasive procedures such as removing oocytes from a woman’s ovaries, fertilize them outside of the body and then transfer the embryos back to the uterus a few days later. These difficulties demand rethinking of assisted fertilization and the sought after novel approaches that offer more natural procedures with high success rate. Hence, we propose untethered medical microbots to assist sperm cells to fertilize an oocyte in living organisms (mice model). The MicroRepro project will bring advances in areas such as bioimaging, nanomaterials science and fundamental biology, boosting the whole field of medical microbots in the process, as was recently highlighted by the PI in an extended comment [Nature 545, 406(2017)]. The PI has decisively contributed to the field of microrobotics and invented the sperm-robot (Spermbot) concept together with his team in two previous patent applications and several publications. The mere concept has attracted worldwide attention. However, even in vitro fertilization has never been achieved – therefore, targeting the challenges leading to the first spermbot fertilization will be the main objective of this project.
Summary
Infertility is a health issue with sociological and psychological implications that affects approximately 50 million couples worldwide and therefore receives global attention. Among fertility issues, male infertility is diagnosed in about 40% of all cases and the major causes are poor motility of spermatozoa (asthenospermia), low sperm count (oligospermia), abnormal sperm morphology (teratospermia) and/or combinations of these, leading to their inability to fertilize an oocyte. Such problems have been mainly addressed by artificial insemination (AI) and in vitro fertilization (IVF). AI involves introducing sperms into a woman’s uterus with a medical instrument, but its applicability is limited and its success rate is below 30%. In contrast, IVF and intracytoplasmic sperm injection can be more effective but implicate more invasive procedures such as removing oocytes from a woman’s ovaries, fertilize them outside of the body and then transfer the embryos back to the uterus a few days later. These difficulties demand rethinking of assisted fertilization and the sought after novel approaches that offer more natural procedures with high success rate. Hence, we propose untethered medical microbots to assist sperm cells to fertilize an oocyte in living organisms (mice model). The MicroRepro project will bring advances in areas such as bioimaging, nanomaterials science and fundamental biology, boosting the whole field of medical microbots in the process, as was recently highlighted by the PI in an extended comment [Nature 545, 406(2017)]. The PI has decisively contributed to the field of microrobotics and invented the sperm-robot (Spermbot) concept together with his team in two previous patent applications and several publications. The mere concept has attracted worldwide attention. However, even in vitro fertilization has never been achieved – therefore, targeting the challenges leading to the first spermbot fertilization will be the main objective of this project.
Max ERC Funding
2 496 141 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
Project acronym MMAF
Project Novel multimodal approach to atrial fibrillation risk assessment and identification of targets for prevention by interdisciplinary exploitation of omics, advanced electrocardiography, and imaging
Researcher (PI) Renate Bonin-Geb.Schnabel
Host Institution (HI) UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary There is a growing need for novel risk schemes in atrial fibrillation (AF) to permit prevention, contribute to a better understanding of the pathophysiology, and discover targets for individualized treatment.
Primary prevention efforts are scant despite the imminent AF epidemic. In international cohorts I have developed and validated the first risk prediction algorithm. However, it explains only 60% of the attributable risk and efforts at improving discrimination are urgently required.
Therefore, my overall goal is to develop an enhanced risk prediction algorithm based on cutting-edge technology. The specific focus will be on parameters representative of early stages of the disease process and intermediate phenotypes such as atrial electrical and structural remodelling, chronic subclinical inflammation, oxidative stress, and autonomous tone in manifest and incident AF. Subclinical, potentially reversible changes are ideally suited to provide independent information complementary to known risk markers.
My ambitious concept is to choose a multimodal approach in an interdisciplinary team to systematically assess:
1) Blood and tissue omics (genomics, expression, proteomics, metabolomics),
2) Advanced electrocardiography,
3) Imaging (echocardiography, cardiac MRI), and
4) Gender applying innovative tools and analyses strategies aimed at a systems biology integration of the accumulated information.
I have collected comprehensive biological and epidemiologic information on distinct AF phenotypes in unique prospective population (N>60,000) and clinical cohorts (N>1,000). We are not aware of other groups with access to such a well-established prospective AF biobank.
Informed by omics, electrocardiography and imaging we will provide pathophysiological insights into the disease process, highlight targets for intervention, and develop a contemporary risk scheme. Our results will lay the ground for rapid translation into clinical practice with significant public health impact.
Summary
There is a growing need for novel risk schemes in atrial fibrillation (AF) to permit prevention, contribute to a better understanding of the pathophysiology, and discover targets for individualized treatment.
Primary prevention efforts are scant despite the imminent AF epidemic. In international cohorts I have developed and validated the first risk prediction algorithm. However, it explains only 60% of the attributable risk and efforts at improving discrimination are urgently required.
Therefore, my overall goal is to develop an enhanced risk prediction algorithm based on cutting-edge technology. The specific focus will be on parameters representative of early stages of the disease process and intermediate phenotypes such as atrial electrical and structural remodelling, chronic subclinical inflammation, oxidative stress, and autonomous tone in manifest and incident AF. Subclinical, potentially reversible changes are ideally suited to provide independent information complementary to known risk markers.
My ambitious concept is to choose a multimodal approach in an interdisciplinary team to systematically assess:
1) Blood and tissue omics (genomics, expression, proteomics, metabolomics),
2) Advanced electrocardiography,
3) Imaging (echocardiography, cardiac MRI), and
4) Gender applying innovative tools and analyses strategies aimed at a systems biology integration of the accumulated information.
I have collected comprehensive biological and epidemiologic information on distinct AF phenotypes in unique prospective population (N>60,000) and clinical cohorts (N>1,000). We are not aware of other groups with access to such a well-established prospective AF biobank.
Informed by omics, electrocardiography and imaging we will provide pathophysiological insights into the disease process, highlight targets for intervention, and develop a contemporary risk scheme. Our results will lay the ground for rapid translation into clinical practice with significant public health impact.
Max ERC Funding
1 999 305 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym MOPIT
Project Molecular photoacoustic imaging of stem-cell driven tissue regeneration
Researcher (PI) Gottfried Jan Laufer
Host Institution (HI) TECHNISCHE UNIVERSITAT BERLIN
Call Details Starting Grant (StG), LS7, ERC-2011-StG_20101109
Summary "I propose to develop a new generation of molecular photoacoustic imaging technologies and methods capable of detecting single deep tissue cells in preclinical studies of tissue regeneration. In order to achieve this goal, an interdisciplinary research programme involving physicists, engineers and life scientists is required to address the following objectives: 1) the development of novel photoacoustic imaging technology that provides high sensitivity and acquisition speed, 2) the development of the theoretical framework and experimental methods for quantitative imaging, 3) the development of novel genetically expressed reporters, and 4) the preclinical application in small animal models of tissue regeneration. This will result in a preclinical imaging modality has the potential to combine single cell sensitivity and microscale spatial resolution in deep (centimetre range) tissue regions with molecular, physiological, and anatomical imaging capabilities. The instrumentation and methodologies developed in this project will be applied to noninvasive, longitudinal, and quantitative studies of stem cell driven tissue regeneration, such as angiogenesis in bone fractures and muscle trauma. It will allow the detection and tracking of single stem cells and the probing of stem cell function. This will provide unprecedented opportunities for correlating cellular localization, migration, and function and with anatomical changes - knowledge that can be exploited to develop novel drugs and cell-based clinical therapies. Crucially, the technologies and methodologies developed in this project will be directly applicable to a wide range of other fields of the life sciences, such as cancer research and neurology."
Summary
"I propose to develop a new generation of molecular photoacoustic imaging technologies and methods capable of detecting single deep tissue cells in preclinical studies of tissue regeneration. In order to achieve this goal, an interdisciplinary research programme involving physicists, engineers and life scientists is required to address the following objectives: 1) the development of novel photoacoustic imaging technology that provides high sensitivity and acquisition speed, 2) the development of the theoretical framework and experimental methods for quantitative imaging, 3) the development of novel genetically expressed reporters, and 4) the preclinical application in small animal models of tissue regeneration. This will result in a preclinical imaging modality has the potential to combine single cell sensitivity and microscale spatial resolution in deep (centimetre range) tissue regions with molecular, physiological, and anatomical imaging capabilities. The instrumentation and methodologies developed in this project will be applied to noninvasive, longitudinal, and quantitative studies of stem cell driven tissue regeneration, such as angiogenesis in bone fractures and muscle trauma. It will allow the detection and tracking of single stem cells and the probing of stem cell function. This will provide unprecedented opportunities for correlating cellular localization, migration, and function and with anatomical changes - knowledge that can be exploited to develop novel drugs and cell-based clinical therapies. Crucially, the technologies and methodologies developed in this project will be directly applicable to a wide range of other fields of the life sciences, such as cancer research and neurology."
Max ERC Funding
1 622 736 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym MRexcite
Project Unlocking the potential of ultra-high-field MRI through manipulation of radiofrequency excitation fields in human tissue
Researcher (PI) Mark Edward Ladd
Host Institution (HI) DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Call Details Advanced Grant (AdG), LS7, ERC-2011-ADG_20110310
Summary In the past three decades, magnetic resonance imaging (MRI) has become a vital tool for clinical diagnosis and research. A major current trend is the introduction of magnets with much more powerful static magnetic fields, including magnets at 7 Tesla (7T) and higher. Advantages of higher magnetic fields include higher signal-to-noise ratios enabling improved spatial and temporal resolution, and new, unique tissue contrasts due to enhanced sensitivity to tissue susceptibility differences.
Unfortunately, the radiofrequency (RF) fields used to excite tissue at higher magnetic fields are subject to interference and penetration effects, leading to signal dropouts which vary from subject to subject depending on body habitus. These effects imply that the inherent advantages of 7T often cannot be leveraged to realise practical imaging benefits. A fair evaluation of the diagnostic potential of 7T cannot be achieved, as image quality improvements are handicapped and often counteracted by these unresolved technical hurdles. 7T MRI cannot be considered for routine clinical use or even effectively evaluated for such use until these hurdles have been overcome.
Preliminary research indicates that these effects can be addressed by use of parallel transmission strategies. The goal of the proposed project is to develop a highly optimized multi-channel transmit/receive RF coil for body MRI at 7T. This coil should then be used to exploit and manipulate the complex RF field patterns at 7T using parallel transmission approaches. In contrast to previous approaches, a hybrid method including both static and dynamic shimming of the RF field will be investigated. We hypothesise that such an approach would greatly enhance the flexibility of RF manipulation while limiting overall system complexity. It can be conjectured based on the known properties of ultra-high-field MRI that success would have ground-breaking impact on the diagnosis and characterisation of manifold disease processes.
Summary
In the past three decades, magnetic resonance imaging (MRI) has become a vital tool for clinical diagnosis and research. A major current trend is the introduction of magnets with much more powerful static magnetic fields, including magnets at 7 Tesla (7T) and higher. Advantages of higher magnetic fields include higher signal-to-noise ratios enabling improved spatial and temporal resolution, and new, unique tissue contrasts due to enhanced sensitivity to tissue susceptibility differences.
Unfortunately, the radiofrequency (RF) fields used to excite tissue at higher magnetic fields are subject to interference and penetration effects, leading to signal dropouts which vary from subject to subject depending on body habitus. These effects imply that the inherent advantages of 7T often cannot be leveraged to realise practical imaging benefits. A fair evaluation of the diagnostic potential of 7T cannot be achieved, as image quality improvements are handicapped and often counteracted by these unresolved technical hurdles. 7T MRI cannot be considered for routine clinical use or even effectively evaluated for such use until these hurdles have been overcome.
Preliminary research indicates that these effects can be addressed by use of parallel transmission strategies. The goal of the proposed project is to develop a highly optimized multi-channel transmit/receive RF coil for body MRI at 7T. This coil should then be used to exploit and manipulate the complex RF field patterns at 7T using parallel transmission approaches. In contrast to previous approaches, a hybrid method including both static and dynamic shimming of the RF field will be investigated. We hypothesise that such an approach would greatly enhance the flexibility of RF manipulation while limiting overall system complexity. It can be conjectured based on the known properties of ultra-high-field MRI that success would have ground-breaking impact on the diagnosis and characterisation of manifold disease processes.
Max ERC Funding
2 099 996 €
Duration
Start date: 2012-05-01, End date: 2017-04-30
Project acronym MSOT
Project Next Generation in-vivo imaging platform for post-genome biology and medicine
Researcher (PI) Vasilis Ntziachristos
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS7, ERC-2008-AdG
Summary With re-defined challenges in post-genome biology and medicine related to understanding the regulation and function of genes, proteins and multi-factorial disease, the development of accelerated and quantitative in-vivo observation of functional -omics at different system levels becomes a vital target. This proposal offers to develop therefore a next-generation biomedical imaging platform, designed to radically impact biomedical and drug discovery applications. The imaging strategy aims at resolving powerful optical reporters (fluorescent proteins, nanoparticles, optical probes) with 10-100 micron resolution and femptomole sensitivity through several millimeters to centimeters of tissue. This performance brings unprecedented ability to non-invasively visualize biological and molecular processes in-vivo in intact organisms over time.
To achieve these goals, the proposal considers first the development of multi-spectral opto-acoustic tomography (MSOT) as a high performance method for revolutionizing biomedical imaging. Then, the proposal offers to develop powerful application areas in visualizing functional –omics, disease growth and drug effectiveness. The advancements offered herein can become a highly preferred biomedical imaging modality while offering ground-breaking imaging performance, safe non-ionizing radiation, an easy to disseminate platform, and unparalleled flexibility in capitalizing on powerful optical contrast using molecular reporters.
Summary
With re-defined challenges in post-genome biology and medicine related to understanding the regulation and function of genes, proteins and multi-factorial disease, the development of accelerated and quantitative in-vivo observation of functional -omics at different system levels becomes a vital target. This proposal offers to develop therefore a next-generation biomedical imaging platform, designed to radically impact biomedical and drug discovery applications. The imaging strategy aims at resolving powerful optical reporters (fluorescent proteins, nanoparticles, optical probes) with 10-100 micron resolution and femptomole sensitivity through several millimeters to centimeters of tissue. This performance brings unprecedented ability to non-invasively visualize biological and molecular processes in-vivo in intact organisms over time.
To achieve these goals, the proposal considers first the development of multi-spectral opto-acoustic tomography (MSOT) as a high performance method for revolutionizing biomedical imaging. Then, the proposal offers to develop powerful application areas in visualizing functional –omics, disease growth and drug effectiveness. The advancements offered herein can become a highly preferred biomedical imaging modality while offering ground-breaking imaging performance, safe non-ionizing radiation, an easy to disseminate platform, and unparalleled flexibility in capitalizing on powerful optical contrast using molecular reporters.
Max ERC Funding
1 999 992 €
Duration
Start date: 2009-03-01, End date: 2014-06-30
Project acronym MUMI
Project Multimodal Molecular Imaging
Researcher (PI) Carl Markus Maximilian Schwaiger
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Advanced Grant (AdG), LS7, ERC-2011-ADG_20110310
Summary "Imaging has become an integral part of diagnosis and staging of disease. This proposal aims at the development if innovative imaging methods for the visualization and quantitative assessment of biologic processes in-vivo. The simultaneous MR/PET data acquisition will be employed o integrate structural, physiologic and molecular information for the phenotyping of human disease and therapeutic decision making process. Such multimodality imaging is thought to serve as unique clinical tool to support the realization of personalized medicine."
Summary
"Imaging has become an integral part of diagnosis and staging of disease. This proposal aims at the development if innovative imaging methods for the visualization and quantitative assessment of biologic processes in-vivo. The simultaneous MR/PET data acquisition will be employed o integrate structural, physiologic and molecular information for the phenotyping of human disease and therapeutic decision making process. Such multimodality imaging is thought to serve as unique clinical tool to support the realization of personalized medicine."
Max ERC Funding
2 238 616 €
Duration
Start date: 2012-06-01, End date: 2017-05-31
Project acronym NanoSCAN
Project Developing multi-modality nanomedicines for targeted annotation of oncogenic signaling pathways
Researcher (PI) Jason Philip Holland
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Spatial and temporal changes in the underlying biochemistry of cancer control disease progression and response/resistance to treatment. Developing methods to detect changes in oncogenic signaling at an early stage is vital to further our understanding of cancer, and will advance the next generation of anti-cancer therapies. Nanomedicine is the medical application of nanotechnology to diagnose or treat disease. In light of the recent introduction of tools like Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) scanners, there is now a new opportunity to develop hybrid imaging protocols that can simultaneously take advantage of the functional and anatomic information available from PET/MRI to address changes in oncogenic signaling pathways. The work outlined in this interdisciplinary ERC Project is designed to advance new chemistry and imaging methods to measure changes in oncogenic signaling in various cancers before, during and after treatment using PET/MRI. The long-term goals are to expand the scope and utility of radiolabelled nanomedicines as dual-modality PET/MRI probes for detecting changes in oncogenic signaling in various cancers and develop efficient methods for translating new technologies to the clinic. Successful completion of this ERC Project has the potential to transform personalised clinical management of cancer patients via advanced PET/MRI detection of oncogenic signaling processes.
Summary
Spatial and temporal changes in the underlying biochemistry of cancer control disease progression and response/resistance to treatment. Developing methods to detect changes in oncogenic signaling at an early stage is vital to further our understanding of cancer, and will advance the next generation of anti-cancer therapies. Nanomedicine is the medical application of nanotechnology to diagnose or treat disease. In light of the recent introduction of tools like Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) scanners, there is now a new opportunity to develop hybrid imaging protocols that can simultaneously take advantage of the functional and anatomic information available from PET/MRI to address changes in oncogenic signaling pathways. The work outlined in this interdisciplinary ERC Project is designed to advance new chemistry and imaging methods to measure changes in oncogenic signaling in various cancers before, during and after treatment using PET/MRI. The long-term goals are to expand the scope and utility of radiolabelled nanomedicines as dual-modality PET/MRI probes for detecting changes in oncogenic signaling in various cancers and develop efficient methods for translating new technologies to the clinic. Successful completion of this ERC Project has the potential to transform personalised clinical management of cancer patients via advanced PET/MRI detection of oncogenic signaling processes.
Max ERC Funding
1 700 000 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym NeoNaNo
Project Neoadjuvant Nanomedicines for vascular Normalization
Researcher (PI) Twan Gerardus Gertrudis Maria Lammers
Host Institution (HI) UNIVERSITAETSKLINIKUM AACHEN
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary The aim of my proposal is to establish ‘Neoadjuvant Nanomedicines for vascular Normalization’ (NeoNaNo) as a novel concept for improving the efficacy of combined modality anticancer therapy. This concept is radically different from all other drug targeting approaches evaluated to date, since nanomedicines are not used to directly improve drug delivery to tumors, but to normalize the tumor vasculature, and to thereby indirectly improve drug (and oxygen) delivery. The need for such an alternative concept can be exemplified by taking the (pre-) clinical performance of nanomedicines into account: whereas in animal models, they generally improve both the efficacy and the tolerability of chemotherapeutic drugs, in patients, they often only attenuate the toxicity of the intervention, and they fail to improve the efficacy of the drug. To overcome this shortcoming, I here propose to use corticosteroid-containing nanomedicines, targeted to tumor-associated macrophages (TAM), to inhibit pro-inflammatory and pro-angiogenic signaling by TAM, and to thereby homogenize the tumor vasculature, increase tumor perfusion and reduce the interstitial fluid pressure. As a result of this, the tumor accumulation, intratumoral distribution and antitumor efficacy of subsequently administered chemotherapeutics, as well as of radiotherapy (because of enhanced oxygen delivery) can be substantially improved. To achieve these goals, liposomal, polymeric and micellar corticosteroids, several different animal models, and several different imaging agents and techniques will be used to (I) visualize and optimize nanomedicine-mediated vascular normalization; to (II) potentiate chemotherapy; and to (III) potentiate radiotherapy. These efforts will not only provide a solid basis for a completely new paradigm in nanomedicine research, but they will also result in novel, broadly applicable and clinically highly relevant combination regimens for improving the treatment of advanced solid malignancies.
Summary
The aim of my proposal is to establish ‘Neoadjuvant Nanomedicines for vascular Normalization’ (NeoNaNo) as a novel concept for improving the efficacy of combined modality anticancer therapy. This concept is radically different from all other drug targeting approaches evaluated to date, since nanomedicines are not used to directly improve drug delivery to tumors, but to normalize the tumor vasculature, and to thereby indirectly improve drug (and oxygen) delivery. The need for such an alternative concept can be exemplified by taking the (pre-) clinical performance of nanomedicines into account: whereas in animal models, they generally improve both the efficacy and the tolerability of chemotherapeutic drugs, in patients, they often only attenuate the toxicity of the intervention, and they fail to improve the efficacy of the drug. To overcome this shortcoming, I here propose to use corticosteroid-containing nanomedicines, targeted to tumor-associated macrophages (TAM), to inhibit pro-inflammatory and pro-angiogenic signaling by TAM, and to thereby homogenize the tumor vasculature, increase tumor perfusion and reduce the interstitial fluid pressure. As a result of this, the tumor accumulation, intratumoral distribution and antitumor efficacy of subsequently administered chemotherapeutics, as well as of radiotherapy (because of enhanced oxygen delivery) can be substantially improved. To achieve these goals, liposomal, polymeric and micellar corticosteroids, several different animal models, and several different imaging agents and techniques will be used to (I) visualize and optimize nanomedicine-mediated vascular normalization; to (II) potentiate chemotherapy; and to (III) potentiate radiotherapy. These efforts will not only provide a solid basis for a completely new paradigm in nanomedicine research, but they will also result in novel, broadly applicable and clinically highly relevant combination regimens for improving the treatment of advanced solid malignancies.
Max ERC Funding
1 356 000 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym NEUROPRECISE
Project Precision medicine in traumatic brain injury using individual neurosteroid response
Researcher (PI) Inga Katharina KOERTE
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Traumatic brain injury (TBI) is very common and affects 1.8 million Europeans seeking medical help each year. TBI is a major challenge for healthcare providers and poses an enormous economic burden. For decades, TBI has been characterized by severity of symptoms for diagnosis, prognosis, and therapy. However, this classification system is limited since it does not allow to predict long-term outcome after TBI. This state of affairs thus hinders the advancement of TBI research and the development of therapies. The field is thus in dire need of a novel understanding and classification of the individual’s response to brain injury and, most importantly, a fresh perspective on potential targets for effective treatment and prevention of long-term impairment.
My main hypothesis is that brain injury leads to a neurosteroid response with inter-individual variability and that this response is associated with the trajectory of recovery. I further hypothesize, that the most vulnerable patient cohorts, such as adolescent girls, show distinct patterns of neurosteroid response associated with an increased risk for persistent symptoms.
NEUROPRECISE proposes a longitudinal cohort study 1) to characterize neurosteroid response with respect to age and sex in children and adolescents with TBI, 2) to evaluate the association of the neuroimaging derived individual injury profile with neurosteroid response, and 3) to explore individual differences in neurosteroid response as a potential target for acute therapy and prevention of chronic symptoms with respect to age and sex in a rodent model.
NEUROPRECISE will overcome a critical barrier towards the treatment of TBI by establishing a novel, biological-driven way to stratify TBI patients based on inter-individual differences in the response to TBI. By exploring the individual neurosteroid response as potential therapeutic target, NEUROPRECISE will bring the power of precision medicine to neurotrauma research.
Summary
Traumatic brain injury (TBI) is very common and affects 1.8 million Europeans seeking medical help each year. TBI is a major challenge for healthcare providers and poses an enormous economic burden. For decades, TBI has been characterized by severity of symptoms for diagnosis, prognosis, and therapy. However, this classification system is limited since it does not allow to predict long-term outcome after TBI. This state of affairs thus hinders the advancement of TBI research and the development of therapies. The field is thus in dire need of a novel understanding and classification of the individual’s response to brain injury and, most importantly, a fresh perspective on potential targets for effective treatment and prevention of long-term impairment.
My main hypothesis is that brain injury leads to a neurosteroid response with inter-individual variability and that this response is associated with the trajectory of recovery. I further hypothesize, that the most vulnerable patient cohorts, such as adolescent girls, show distinct patterns of neurosteroid response associated with an increased risk for persistent symptoms.
NEUROPRECISE proposes a longitudinal cohort study 1) to characterize neurosteroid response with respect to age and sex in children and adolescents with TBI, 2) to evaluate the association of the neuroimaging derived individual injury profile with neurosteroid response, and 3) to explore individual differences in neurosteroid response as a potential target for acute therapy and prevention of chronic symptoms with respect to age and sex in a rodent model.
NEUROPRECISE will overcome a critical barrier towards the treatment of TBI by establishing a novel, biological-driven way to stratify TBI patients based on inter-individual differences in the response to TBI. By exploring the individual neurosteroid response as potential therapeutic target, NEUROPRECISE will bring the power of precision medicine to neurotrauma research.
Max ERC Funding
1 499 998 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym NOVA
Project Non-coding RNA in Vascular Ageing
Researcher (PI) Reinier Boon
Host Institution (HI) JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN
Call Details Starting Grant (StG), LS7, ERC-2014-STG
Summary Life expectancy in the European Union is rising and the prevalence of age-induced cardiovascular disease increases concomitantly. Endothelial dysfunction is a hallmark of aging in the vasculature and is the underlying cause of many cardiovascular disorders, like hypertension, acute myocardial infarction and stroke. This proposal aims to better understand the molecular mechanisms behind aging that lead to endothelial dysfunction.
Non-coding RNAs are emerging as novel key regulators of cellular functions and we hypothesize that non-coding RNAs contribute to vascular aging. Preliminary experiments show that several long non-coding RNAs (lncRNAs) are regulated during aging of the cardiovascular system, including the lncRNA H19. We propose to extensively characterize the role of H19 in endothelial aging and to identify other lncRNAs that are involved in vascular aging. We will use state-of-the-art in vitro and in vivo models to assess endothelial aging and function upon gain-of-function and loss-of-function of lncRNAs.
Understanding the role that H19 and other lncRNAs play in aging endothelium will highlight novel potential therapeutic targets to attenuate age-induced endothelial dysfunction. The focus on aging will also yield insight in molecular mechanisms that may have been overlooked when studying endothelial function in young cells or organisms.
Summary
Life expectancy in the European Union is rising and the prevalence of age-induced cardiovascular disease increases concomitantly. Endothelial dysfunction is a hallmark of aging in the vasculature and is the underlying cause of many cardiovascular disorders, like hypertension, acute myocardial infarction and stroke. This proposal aims to better understand the molecular mechanisms behind aging that lead to endothelial dysfunction.
Non-coding RNAs are emerging as novel key regulators of cellular functions and we hypothesize that non-coding RNAs contribute to vascular aging. Preliminary experiments show that several long non-coding RNAs (lncRNAs) are regulated during aging of the cardiovascular system, including the lncRNA H19. We propose to extensively characterize the role of H19 in endothelial aging and to identify other lncRNAs that are involved in vascular aging. We will use state-of-the-art in vitro and in vivo models to assess endothelial aging and function upon gain-of-function and loss-of-function of lncRNAs.
Understanding the role that H19 and other lncRNAs play in aging endothelium will highlight novel potential therapeutic targets to attenuate age-induced endothelial dysfunction. The focus on aging will also yield insight in molecular mechanisms that may have been overlooked when studying endothelial function in young cells or organisms.
Max ERC Funding
1 499 694 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym Novel asthma therapy
Project Biocompatible nanoparticles for T cell targeted siRNA delivery as novel asthma therapy
Researcher (PI) Olivia Merkel
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), LS7, ERC-2014-STG
Summary The aim of this proposal is to engineer biocompatible nanoparticles that deliver short interfering RNA (siRNA) to activated T cells (ATCs) for the downregulation of the Type 2 T helper cell (Th2) transcription factor GATA-3. By downregulating GATA-3 with siRNA, which regulates the secretion of proinflammatory cytokines in chronic inflammatory diseases such as asthma, the activation of their downstream inflammatory cascades can be prevented. However, T cells are hard-to-transfect cells which are not readily accessible for nucleic acid based therapeutics. I am the first to have demonstrated successful and targeted siRNA delivery to ATCs ex vivo and in vivo for specific GATA-3 knockdown without delivering siRNA to naive T cells. Thus, I can avoid general immune suppression. This was achieved by engineering targeted siRNA delivery systems based on low molecular weight polyethylenimine (LMW-PEI) which form nanoparticles with siRNA and successfully deliver the latter to ATCs. The targeting approach was realized by coupling transferrin to LMW-PEI and by optimizing the coupling chemistry. I have demonstrated specific delivery to ATCs in a mouse model of allergic asthma and have screened siRNA sequences for efficient GATA-3 knockdown. The nanoparticles were administered locally to the lung to prevent the first-pass effect in the liver. The LMW-PEI based nanocarriers were very well tolerated in healthy animals, however, potentially caused additional proinflammatory effects in the asthma model.
Therefore, I will engineer nanocarriers that do not only specifically deliver siRNA to ATCs but are also biocompatible in a diseased state of the lung. I will use oligospermines, which are tetramers and octamers of spermine, an endogenous polyamine, and apply the optimized coupling strategy to target the spermine based nanocarriers to ATCs for therapeutic GATA-3 knockdown. To obtain clinically relevant formulations, I will produce inhalable powders of these nanocarriers.
Summary
The aim of this proposal is to engineer biocompatible nanoparticles that deliver short interfering RNA (siRNA) to activated T cells (ATCs) for the downregulation of the Type 2 T helper cell (Th2) transcription factor GATA-3. By downregulating GATA-3 with siRNA, which regulates the secretion of proinflammatory cytokines in chronic inflammatory diseases such as asthma, the activation of their downstream inflammatory cascades can be prevented. However, T cells are hard-to-transfect cells which are not readily accessible for nucleic acid based therapeutics. I am the first to have demonstrated successful and targeted siRNA delivery to ATCs ex vivo and in vivo for specific GATA-3 knockdown without delivering siRNA to naive T cells. Thus, I can avoid general immune suppression. This was achieved by engineering targeted siRNA delivery systems based on low molecular weight polyethylenimine (LMW-PEI) which form nanoparticles with siRNA and successfully deliver the latter to ATCs. The targeting approach was realized by coupling transferrin to LMW-PEI and by optimizing the coupling chemistry. I have demonstrated specific delivery to ATCs in a mouse model of allergic asthma and have screened siRNA sequences for efficient GATA-3 knockdown. The nanoparticles were administered locally to the lung to prevent the first-pass effect in the liver. The LMW-PEI based nanocarriers were very well tolerated in healthy animals, however, potentially caused additional proinflammatory effects in the asthma model.
Therefore, I will engineer nanocarriers that do not only specifically deliver siRNA to ATCs but are also biocompatible in a diseased state of the lung. I will use oligospermines, which are tetramers and octamers of spermine, an endogenous polyamine, and apply the optimized coupling strategy to target the spermine based nanocarriers to ATCs for therapeutic GATA-3 knockdown. To obtain clinically relevant formulations, I will produce inhalable powders of these nanocarriers.
Max ERC Funding
2 000 000 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym ONCOINTRABODY
Project Targeting common oncogenes with intracellular monobodies
Researcher (PI) Oliver Denis Hantschel
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Consolidator Grant (CoG), LS7, ERC-2015-CoG
Summary Oncogenic signalling networks display a remarkable degree of plasticity. Despite only a limited number of alterations in oncogenes and tumour suppressor genes in most tumours, the majority of targeted therapeutics (monoclonal antibodies and small-molecule kinase inhibitors) does not strongly improve the survival of cancer patients and suffers from the rapid development of resistance. The rising number of targeted drugs in clinical use inhibits only a very limited number of protein targets (largely kinases). Consequently, most intracellular non-kinase oncoproteins remain untargeted. We have previously established the use of small engineered antibody mimics, termed monobodies, to potently and specifically target intracellular protein-protein interactions mediated by the SH2 domains of oncogenic kinases and phosphatases. Expression of SH2-targeting monobodies resulted in the inhibition of signalling and oncogenesis of these oncoproteins. Here, we aim at developing monobody binders to 10 key intracellular oncoproteins for which no chemical inhibitors exist and testing their activity in cancer cells. To enable a possible clinical translation of monobody-based therapeutics, we will develop methods to deliver monobody proteins into cells, including cell-penetrating peptides, bacterial toxins and biocompatible nanocarriers. 'Mirror-image' monobodies, composed of D-amino acids, will be developed and tested to increase intracellular and plasma stability and to limit immunogenicity. The developed monobodies and delivery systems are planned to be tested in mouse cancer models. Our goal is to establish monobodies as novel class of intracellular protein-based therapeutics. We hope to kick off their use beyond basic research tools towards possible applications in cancer patients. This innovative endeavour uses state-of-the-art protein engineering techniques to address a central problem in cancer medicine and may provide a ground-breaking new approach to target cancer.
Summary
Oncogenic signalling networks display a remarkable degree of plasticity. Despite only a limited number of alterations in oncogenes and tumour suppressor genes in most tumours, the majority of targeted therapeutics (monoclonal antibodies and small-molecule kinase inhibitors) does not strongly improve the survival of cancer patients and suffers from the rapid development of resistance. The rising number of targeted drugs in clinical use inhibits only a very limited number of protein targets (largely kinases). Consequently, most intracellular non-kinase oncoproteins remain untargeted. We have previously established the use of small engineered antibody mimics, termed monobodies, to potently and specifically target intracellular protein-protein interactions mediated by the SH2 domains of oncogenic kinases and phosphatases. Expression of SH2-targeting monobodies resulted in the inhibition of signalling and oncogenesis of these oncoproteins. Here, we aim at developing monobody binders to 10 key intracellular oncoproteins for which no chemical inhibitors exist and testing their activity in cancer cells. To enable a possible clinical translation of monobody-based therapeutics, we will develop methods to deliver monobody proteins into cells, including cell-penetrating peptides, bacterial toxins and biocompatible nanocarriers. 'Mirror-image' monobodies, composed of D-amino acids, will be developed and tested to increase intracellular and plasma stability and to limit immunogenicity. The developed monobodies and delivery systems are planned to be tested in mouse cancer models. Our goal is to establish monobodies as novel class of intracellular protein-based therapeutics. We hope to kick off their use beyond basic research tools towards possible applications in cancer patients. This innovative endeavour uses state-of-the-art protein engineering techniques to address a central problem in cancer medicine and may provide a ground-breaking new approach to target cancer.
Max ERC Funding
1 996 055 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym OPTIM
Project Optimized drug combinations for effective cancer treatment: a personalised approach.
Researcher (PI) Patrycja*Monika Nowak-Sliwinska
Host Institution (HI) UNIVERSITE DE GENEVE
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary This project aims to improve the treatment of metastasized colorectal carcinoma (mCRC), as treatment options after first line chemotherapy are desperately needed. The key to improvement of cancer therapy resides in optimal combination of drugs. Optimally combining drugs is non-trivial due to the large number of possibilities, especially when more than two drugs are combined at various doses. In the current research program I propose to use a differential evolution guided stochastic search algorithm to guide the way in finding optimal combination therapies. In previous research I have applied this feedback system control (FSC) technique to navigate through the enormous parametric space of nine angiostatic drugs at four doses. The straightforward iterative approach of in vitro cell viability testing and algorithm-based analysis identified optimal synergistic low-dose drug combinations. In vivo translation by maintaining the drug dose ratio led to effective anti-cancer activity, without evidence of side-effects.
A new screen for optimal targeted combination treatment of advanced CRC will be performed. A series of 7 genetically different human CRC cell lines will be used in this screen, thus simulating personalized treatment. The optimized combinations will be ‘ratiometrically’ translated into orthotopic and metastasizing preclinical CRC mouse models and tested in parallel to standard chemotherapy regimens. Development of a method for a personalized screen using freshly isolated tumor cells will prepare the technology for application in the clinic.
Using an innovative strategy I previously identified a series of novel markers of the tumor endothelium. After validation of these targets, this project aims for the design of new drugs to be used in a screen for optimal combination therapy for mCRC. The translational and multidisciplinary nature of the current proposal aims for preparing an improved therapeutic combination regimen for testing in cancer patients.
Summary
This project aims to improve the treatment of metastasized colorectal carcinoma (mCRC), as treatment options after first line chemotherapy are desperately needed. The key to improvement of cancer therapy resides in optimal combination of drugs. Optimally combining drugs is non-trivial due to the large number of possibilities, especially when more than two drugs are combined at various doses. In the current research program I propose to use a differential evolution guided stochastic search algorithm to guide the way in finding optimal combination therapies. In previous research I have applied this feedback system control (FSC) technique to navigate through the enormous parametric space of nine angiostatic drugs at four doses. The straightforward iterative approach of in vitro cell viability testing and algorithm-based analysis identified optimal synergistic low-dose drug combinations. In vivo translation by maintaining the drug dose ratio led to effective anti-cancer activity, without evidence of side-effects.
A new screen for optimal targeted combination treatment of advanced CRC will be performed. A series of 7 genetically different human CRC cell lines will be used in this screen, thus simulating personalized treatment. The optimized combinations will be ‘ratiometrically’ translated into orthotopic and metastasizing preclinical CRC mouse models and tested in parallel to standard chemotherapy regimens. Development of a method for a personalized screen using freshly isolated tumor cells will prepare the technology for application in the clinic.
Using an innovative strategy I previously identified a series of novel markers of the tumor endothelium. After validation of these targets, this project aims for the design of new drugs to be used in a screen for optimal combination therapy for mCRC. The translational and multidisciplinary nature of the current proposal aims for preparing an improved therapeutic combination regimen for testing in cancer patients.
Max ERC Funding
1 199 436 €
Duration
Start date: 2016-05-01, End date: 2020-04-30
Project acronym OPTOACOUSTOGENETICS
Project Hybrid Volumetric Optoacoustic-Ultrasound Tomography for Noninvasive Large-Scale Recording of Brain Activity with High Spatiotemporal Resolution
Researcher (PI) Daniel Razansky
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Call Details Consolidator Grant (CoG), LS7, ERC-2015-CoG
Summary Non-invasive observation of fast spatiotemporal activity patterns of large neural populations distributed over entire brains is a longstanding goal of neuroscience. Not only would such abilities significantly promote our knowledge on brain function and its pathophysiology but they are also expected to accelerate development of novel therapies targeting neurological and neuropsychiatric disorders. The progress is hampered by the limited capacity of state-of-the-art functional neuroimaging tools, which do not permit simultaneous monitoring of whole-brain activity with an adequate spatiotemporal resolution. Our recently developed five-dimensional optoacoustic tomography technique is ideally poised to overcome these limitations – it has shown excellent capacity for imaging intrinsic contrast in entire brains of vertebrates and rodents non-invasively; delivers unmatched temporal resolution in the milliseconds range for true volumetric imaging in real time; capable of label-free observations of hemodynamic changes and sensitive to genetic markers of neural activity.
Yet, several fundamental challenges ought to be addressed before true potential of optoacoustic functional neuroimaging is unveiled. First, optoacoustic monitoring of fast neural activation under physiologically relevant stimuli and in real disease models has not been achieved. Furthermore, a variety of acoustic effects introduced by the skull compromise performance of optoacoustics in transcranial imaging of murine models, further hindering its clinical translation potential. Finally, technology needs to be developed that can deliver information from single neurons while maintaining high volumetric imaging speed. By resolving those challenges, the current project will yield a unique and groundbreaking functional neuroimaging method that can truly transform the existing paradigms in neuroscience by delivering real time information from hundreds of thousands or even millions of neurons simultaneously.
Summary
Non-invasive observation of fast spatiotemporal activity patterns of large neural populations distributed over entire brains is a longstanding goal of neuroscience. Not only would such abilities significantly promote our knowledge on brain function and its pathophysiology but they are also expected to accelerate development of novel therapies targeting neurological and neuropsychiatric disorders. The progress is hampered by the limited capacity of state-of-the-art functional neuroimaging tools, which do not permit simultaneous monitoring of whole-brain activity with an adequate spatiotemporal resolution. Our recently developed five-dimensional optoacoustic tomography technique is ideally poised to overcome these limitations – it has shown excellent capacity for imaging intrinsic contrast in entire brains of vertebrates and rodents non-invasively; delivers unmatched temporal resolution in the milliseconds range for true volumetric imaging in real time; capable of label-free observations of hemodynamic changes and sensitive to genetic markers of neural activity.
Yet, several fundamental challenges ought to be addressed before true potential of optoacoustic functional neuroimaging is unveiled. First, optoacoustic monitoring of fast neural activation under physiologically relevant stimuli and in real disease models has not been achieved. Furthermore, a variety of acoustic effects introduced by the skull compromise performance of optoacoustics in transcranial imaging of murine models, further hindering its clinical translation potential. Finally, technology needs to be developed that can deliver information from single neurons while maintaining high volumetric imaging speed. By resolving those challenges, the current project will yield a unique and groundbreaking functional neuroimaging method that can truly transform the existing paradigms in neuroscience by delivering real time information from hundreds of thousands or even millions of neurons simultaneously.
Max ERC Funding
1 997 715 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym OVOC
Project Ultra Fast Magnetic Resonance Imaging using One-Voxel-One-Coil Acquisition
Researcher (PI) Jürgen Hennig
Host Institution (HI) UNIVERSITAETSKLINIKUM FREIBURG
Call Details Advanced Grant (AdG), LS7, ERC-2008-AdG
Summary The proposal is aimed at the development of ultrafast Magnetic Resonance Imaging (MRI) for applications in neuroscience, neurology and oncology. The methodology used is based on the principle of one-voxel-one-coil acquisition in which the sensitive volumes of arrays containing a large number of small receiver coils is used as primary source of spatial localization. This allows to achieve acquisition speed >> 10 fps and opens up new windows of application for MRI. Within this proposal research will be aimed at two areas of application: For investigation of fast physiological events in the brain, applications based on the observation of fast spatiotemporal events by MR-encephalography (MREG) will be developed. MREG will be used for detailed quantitative measurement of differential cortical response during activation of cortical networks by complex stimuli. Primary areas of interest will be the investigation of spatiotemporal response in visual perception, visual and auditory cued tasks and during language processing. In addition to quantitative mapping of response, map functional connectivity with and without correlation with ECG will be investigated. For neurological applications we will use the very high sensitivity of MREG to detect arterial pulsatility in order to generate quantitative, three-dimensional maps of hemodynamic function. Clinical applications for examination of patients with stroke, ischemia, vascular disease and vascular pathologies will be developed. The principles of OVOC-measurements will also be applied in oncology for measurements of fast intrinsic and stimulated physiological events like dynamic measurements of blood flow, tissue permeability and oxygenation in tumors and metastasis. Spectroscopic OVOC-measurements will be developed to observe metabolic turnover. All experiments will be performed both in humans and animal models. Highly localized experiments will be performed using microcoil arrays currently under development.
Summary
The proposal is aimed at the development of ultrafast Magnetic Resonance Imaging (MRI) for applications in neuroscience, neurology and oncology. The methodology used is based on the principle of one-voxel-one-coil acquisition in which the sensitive volumes of arrays containing a large number of small receiver coils is used as primary source of spatial localization. This allows to achieve acquisition speed >> 10 fps and opens up new windows of application for MRI. Within this proposal research will be aimed at two areas of application: For investigation of fast physiological events in the brain, applications based on the observation of fast spatiotemporal events by MR-encephalography (MREG) will be developed. MREG will be used for detailed quantitative measurement of differential cortical response during activation of cortical networks by complex stimuli. Primary areas of interest will be the investigation of spatiotemporal response in visual perception, visual and auditory cued tasks and during language processing. In addition to quantitative mapping of response, map functional connectivity with and without correlation with ECG will be investigated. For neurological applications we will use the very high sensitivity of MREG to detect arterial pulsatility in order to generate quantitative, three-dimensional maps of hemodynamic function. Clinical applications for examination of patients with stroke, ischemia, vascular disease and vascular pathologies will be developed. The principles of OVOC-measurements will also be applied in oncology for measurements of fast intrinsic and stimulated physiological events like dynamic measurements of blood flow, tissue permeability and oxygenation in tumors and metastasis. Spectroscopic OVOC-measurements will be developed to observe metabolic turnover. All experiments will be performed both in humans and animal models. Highly localized experiments will be performed using microcoil arrays currently under development.
Max ERC Funding
2 495 600 €
Duration
Start date: 2009-09-01, End date: 2015-02-28
Project acronym PEARL
Project Priming epithelial cell activation to regenerate the lung
Researcher (PI) Melanie Königshoff
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Chronic obstructive pulmonary disease (COPD), a global health problem, will be the third leading cause of death by 2020. No effective therapy exists for COPD, which is characterized by a progressive loss of lung tissue, in particular functional alveolar epithelium, due to the inability of the lung to regenerate. Thus, regeneration of functional lung tissue would be a tremendous step forward, which has not been demonstrated as of yet.
The alveolar epithelium is essential for normal lung function and composed of alveolar type I (ATI) and type II (ATII) cells. ATII cells serve as progenitors for alveolar epithelial restoration via differentiation into ATI cells. Induction of lung regeneration requires a tight interplay between initiating and differentiating factors acting on the alveolar epithelium.
The overall aim of this proposal is to explore the regenerative potential of the adult human lung, driven by the alveolar epithelium. We will utilize an ex vivo lung regeneration model, characterize ATI/II cells in diseased lungs, and explore novel initiating and differentiating factors in vivo and ex vivo.
WNT/²-catenin signaling is a promising initiating factor for lung regeneration. We have recently demonstrated a crucial role of WNT/²-catenin signaling in alveolar epithelial cell repair in lung disease. Further, embryos lacking WNT2/2b expression exhibited complete lung agenesis, demonstrating the requirement of WNT/²-catenin signaling in lung generation. We will explore WNT/²-catenin signaling in ATI/II cells, and the regenerative potential thereof. We will analyze the ATI/II cell phenotype in mouse and human COPD specimen, to identify novel differentiation factors facilitating lung regeneration.
We will consolidate our findings by testing the therapeutic applicability of initiating and differentiating factors in COPD in our ex vivo human lung regeneration model. This will lead to reliable and validated results that will be successfully translated into the clinic.
Summary
Chronic obstructive pulmonary disease (COPD), a global health problem, will be the third leading cause of death by 2020. No effective therapy exists for COPD, which is characterized by a progressive loss of lung tissue, in particular functional alveolar epithelium, due to the inability of the lung to regenerate. Thus, regeneration of functional lung tissue would be a tremendous step forward, which has not been demonstrated as of yet.
The alveolar epithelium is essential for normal lung function and composed of alveolar type I (ATI) and type II (ATII) cells. ATII cells serve as progenitors for alveolar epithelial restoration via differentiation into ATI cells. Induction of lung regeneration requires a tight interplay between initiating and differentiating factors acting on the alveolar epithelium.
The overall aim of this proposal is to explore the regenerative potential of the adult human lung, driven by the alveolar epithelium. We will utilize an ex vivo lung regeneration model, characterize ATI/II cells in diseased lungs, and explore novel initiating and differentiating factors in vivo and ex vivo.
WNT/²-catenin signaling is a promising initiating factor for lung regeneration. We have recently demonstrated a crucial role of WNT/²-catenin signaling in alveolar epithelial cell repair in lung disease. Further, embryos lacking WNT2/2b expression exhibited complete lung agenesis, demonstrating the requirement of WNT/²-catenin signaling in lung generation. We will explore WNT/²-catenin signaling in ATI/II cells, and the regenerative potential thereof. We will analyze the ATI/II cell phenotype in mouse and human COPD specimen, to identify novel differentiation factors facilitating lung regeneration.
We will consolidate our findings by testing the therapeutic applicability of initiating and differentiating factors in COPD in our ex vivo human lung regeneration model. This will lead to reliable and validated results that will be successfully translated into the clinic.
Max ERC Funding
1 291 670 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym PHARMS
Project Bacteriophage inhibition of antibiotic-resistant pathogenic microbes and founding for novel therapeutic strategies
Researcher (PI) Li DENG
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Emergence of antimicrobial resistance (AMR) is a grand scientific challenge of our time that has killed more than 700,000 people worldwide. Phage therapy, a promising complement to antibiotics, utilizes viruses of bacteria (bacteriophages) or phage-derived inhibitors as natural ways to fight AMR. The main obstacles in the clinical application of phage-based AMR therapy are the limited number of phage isolates and the unknown molecular mechanisms of phage-delivered bactericidal action. Building on the recent advances of my group in high-throughput, culture-independent but host-targeted methodologies, PHARMS aims to deploy a revolutionary approach: to screen for all possible phages of a resistant bacterial isolate, characterize multiple lines of their bactericidal functions, and use this information for the design of a whole battery of phage-based therapies that employ multifaceted modes of action.
Using an interdisciplinary research plan, PHARMS will discover phage-specific bactericidal action modes at all possible levels ranging from nucleotide sequence and transcription to translation, in order to elucidate the molecular mechanisms driving phage-mediated inhibition of AMR Acinetobacter baumannii, Helicobacter pylori, & Haemophilus influenzae (WP1). These discoveries, together with novel synthetic biology tools, will enable us to engineer an array of phage vectors that mimic phage-deployed bactericidal modes discovered under WP1, including transport of alien genes to deliver bactericidal effects (WP2). PHARMS will provide molecular confirmation and in vitro & in vivo validation of the functions of phage-encoded bactericidal peptides and enzymes (WP3). By elucidating universal and specific mechanisms of phage-delivered inhibition of AMR pathogens, PHARMS is positioned to provide the rational framework for the design of novel therapeutic strategies aimed at treating common and life-threatening infectious diseases.
Summary
Emergence of antimicrobial resistance (AMR) is a grand scientific challenge of our time that has killed more than 700,000 people worldwide. Phage therapy, a promising complement to antibiotics, utilizes viruses of bacteria (bacteriophages) or phage-derived inhibitors as natural ways to fight AMR. The main obstacles in the clinical application of phage-based AMR therapy are the limited number of phage isolates and the unknown molecular mechanisms of phage-delivered bactericidal action. Building on the recent advances of my group in high-throughput, culture-independent but host-targeted methodologies, PHARMS aims to deploy a revolutionary approach: to screen for all possible phages of a resistant bacterial isolate, characterize multiple lines of their bactericidal functions, and use this information for the design of a whole battery of phage-based therapies that employ multifaceted modes of action.
Using an interdisciplinary research plan, PHARMS will discover phage-specific bactericidal action modes at all possible levels ranging from nucleotide sequence and transcription to translation, in order to elucidate the molecular mechanisms driving phage-mediated inhibition of AMR Acinetobacter baumannii, Helicobacter pylori, & Haemophilus influenzae (WP1). These discoveries, together with novel synthetic biology tools, will enable us to engineer an array of phage vectors that mimic phage-deployed bactericidal modes discovered under WP1, including transport of alien genes to deliver bactericidal effects (WP2). PHARMS will provide molecular confirmation and in vitro & in vivo validation of the functions of phage-encoded bactericidal peptides and enzymes (WP3). By elucidating universal and specific mechanisms of phage-delivered inhibition of AMR pathogens, PHARMS is positioned to provide the rational framework for the design of novel therapeutic strategies aimed at treating common and life-threatening infectious diseases.
Max ERC Funding
1 499 650 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym PhaseX
Project Phase contrast X-ray imaging for medicine
Researcher (PI) Marco Stampanoni
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary The goal of this grant is to introduce grating-based phase contrast enhanced X-ray imaging as a novel diagnostic tool in human medicine. We will first gain fundamental knowledge to master high-energy grating-based phase contrast imaging and develop novel radiological equipment at the demonstrator/prototype level to perform phase contrast enhanced investigation in human patients in-vivo. In a second phase, we will investigate in depth how our novel method applies to a few pivotal medical fields like mammography, vascular- and musculoskeletal diseases. In these areas there is a strong need for radiological investigations with improved density discrimination, specifically for early breast cancer detection, plaques visualization and cartilage, tendons or ligaments imaging. No hospital or clinical infrastructure in the world can perform phase contrast enhanced X-ray radiological investigations: therefore our discoveries will constitute an enormous impact in this field.
Summary
The goal of this grant is to introduce grating-based phase contrast enhanced X-ray imaging as a novel diagnostic tool in human medicine. We will first gain fundamental knowledge to master high-energy grating-based phase contrast imaging and develop novel radiological equipment at the demonstrator/prototype level to perform phase contrast enhanced investigation in human patients in-vivo. In a second phase, we will investigate in depth how our novel method applies to a few pivotal medical fields like mammography, vascular- and musculoskeletal diseases. In these areas there is a strong need for radiological investigations with improved density discrimination, specifically for early breast cancer detection, plaques visualization and cartilage, tendons or ligaments imaging. No hospital or clinical infrastructure in the world can perform phase contrast enhanced X-ray radiological investigations: therefore our discoveries will constitute an enormous impact in this field.
Max ERC Funding
1 499 300 €
Duration
Start date: 2012-11-01, End date: 2017-10-31
Project acronym PICS THERAPY
Project Manipulation of senescence pathways for cancer therapy: from experimental models to clinic
Researcher (PI) Andrea Alimonti
Host Institution (HI) Ente Ospedaliero Cantonale
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary This proposal aims to harness a novel type of senescence that we have identified in response to acute Pten inactivation, and which we believe offers a radical therapeutic approach to target the quiescent cancer stem cell in vivo. In characterizing Pten loss Induced Cellular Senescence, which we have named PICS for short, we have discovered that PICS is distinct from other forms of cellular senescence including oncogene-induced senescence (OIS) and replicative senescence. These distinct differences are characterized by a lack of DNA damage and hyper-replication, breaking the current dogma for senescence induction. The ability to induce senescence, an irreversible growth arrest, in cells by targeting Pten signaling, without a requirement for hyper-replication and DNA damage opens up the possibility to target quiescent cells, including stem cells, that have a low proliferative index. This approach has tremendous therapeutic potential and represents one of the most exciting developments for the advancement of prostate cancer therapy in recent years. Through the manipulation of senescence induction pathways we will identify PICS enhancing drugs and redefine the paradigm for cancer therapy. By developing novel mouse models that target prostate stem cells we will evaluate these PICS pro-senescence drugs in a pre-clinical setting. Finally, these results will be cross referenced with data from human prostate stem cells and we will lay the ground work to translate this to the clinical setting, further developing the clinical potential of these findings to eradicate prostate cancer.
Summary
This proposal aims to harness a novel type of senescence that we have identified in response to acute Pten inactivation, and which we believe offers a radical therapeutic approach to target the quiescent cancer stem cell in vivo. In characterizing Pten loss Induced Cellular Senescence, which we have named PICS for short, we have discovered that PICS is distinct from other forms of cellular senescence including oncogene-induced senescence (OIS) and replicative senescence. These distinct differences are characterized by a lack of DNA damage and hyper-replication, breaking the current dogma for senescence induction. The ability to induce senescence, an irreversible growth arrest, in cells by targeting Pten signaling, without a requirement for hyper-replication and DNA damage opens up the possibility to target quiescent cells, including stem cells, that have a low proliferative index. This approach has tremendous therapeutic potential and represents one of the most exciting developments for the advancement of prostate cancer therapy in recent years. Through the manipulation of senescence induction pathways we will identify PICS enhancing drugs and redefine the paradigm for cancer therapy. By developing novel mouse models that target prostate stem cells we will evaluate these PICS pro-senescence drugs in a pre-clinical setting. Finally, these results will be cross referenced with data from human prostate stem cells and we will lay the ground work to translate this to the clinical setting, further developing the clinical potential of these findings to eradicate prostate cancer.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym PNANOMED
Project Personalized Nanomedicines for Leukemia Patients
Researcher (PI) Michael Heuser
Host Institution (HI) MEDIZINISCHE HOCHSCHULE HANNOVER
Call Details Starting Grant (StG), LS7, ERC-2014-STG
Summary Acute myeloid leukemia (AML) remains a devastating disease, while progress in genetic characterization and nanomedical approaches promise a new era of individualized treatments. To prioritize genetic aberrations in AML for therapeutic targeting and to develop a pipeline for personalized nanomedicines I will i) establish a biobank of transplantable primary human AML xenotransplants, ii) fully characterize the genetic landscape of these leukemias, iii) establish the functional hierarchy of driver and passenger mutations in these human leukemia models, iv) develop highly efficient nanoparticle-siRNA formulations that allow in vivo delivery of siRNA to primary AML blasts, and v) design double specific siRNA-based nanomedicines for improved efficacy and tolerability. The expertise of my research team and my institutional settings and collaborations provide a unique platform to achieve these objectives. My access to freshly isolated leukemia blasts allows efficient establishment of a biobank for AML xenotransplant models. In fact, we can serially transplant and expand primary AML cells in immunodeficient mice. The biobank will be an invaluable resource for pharmaceutical product development. I have extensive experience in the genetic characterization and functional evaluation of leukemic cells, which I will apply to the newly generated human AML models. I will use inducible lentiviral approaches to genetically modify human leukemia cells and observe the functional effects in vivo, to identify the relevant targets for leukemogenicity of each primary AML model. Most importantly, I can formulate nanoparticle-siRNA systems that show unprecedented complete uptake into human leukemia cells in vivo and open the door for specific inhibition of any gene. These established tools provide me with the unique ability to develop a pipeline for individualized nanomedicines that will improve AML treatment and will also have broad applications beyond leukemia treatment.
Summary
Acute myeloid leukemia (AML) remains a devastating disease, while progress in genetic characterization and nanomedical approaches promise a new era of individualized treatments. To prioritize genetic aberrations in AML for therapeutic targeting and to develop a pipeline for personalized nanomedicines I will i) establish a biobank of transplantable primary human AML xenotransplants, ii) fully characterize the genetic landscape of these leukemias, iii) establish the functional hierarchy of driver and passenger mutations in these human leukemia models, iv) develop highly efficient nanoparticle-siRNA formulations that allow in vivo delivery of siRNA to primary AML blasts, and v) design double specific siRNA-based nanomedicines for improved efficacy and tolerability. The expertise of my research team and my institutional settings and collaborations provide a unique platform to achieve these objectives. My access to freshly isolated leukemia blasts allows efficient establishment of a biobank for AML xenotransplant models. In fact, we can serially transplant and expand primary AML cells in immunodeficient mice. The biobank will be an invaluable resource for pharmaceutical product development. I have extensive experience in the genetic characterization and functional evaluation of leukemic cells, which I will apply to the newly generated human AML models. I will use inducible lentiviral approaches to genetically modify human leukemia cells and observe the functional effects in vivo, to identify the relevant targets for leukemogenicity of each primary AML model. Most importantly, I can formulate nanoparticle-siRNA systems that show unprecedented complete uptake into human leukemia cells in vivo and open the door for specific inhibition of any gene. These established tools provide me with the unique ability to develop a pipeline for individualized nanomedicines that will improve AML treatment and will also have broad applications beyond leukemia treatment.
Max ERC Funding
1 499 750 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym PREMSOT
Project Precision Multi-Spectral Optoacoustic Tomography for Discovery Diagnosis and Intervention
Researcher (PI) Vasilis NTZIACHRISTOS
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Call Details Advanced Grant (AdG), LS7, ERC-2015-AdG
Summary The 2008 ERC Advanced Grant multispectral optoacoustic tomography (MSOT) yielded a novel modality for post-genomic small animal optical imaging, >110 peer-reviewed publications and several major awards including the 2014 Germany’s Innovation award. Since 2011 spin-off iThera Medical GmbH commercialized and placed MSOT systems in European, Asian and North American laboratories, making MSOT an international term. MSOT brought unprecedented optical imaging performance now enabling independent discovery and publications from researchers throughout the world.
Compared to other imaging modalities, MSOT uniquely images tissue oxygenation and other vascular and pathophysiology parameters in label-free and portable mode, using safe non-ionizing energy. Therefore, MSOT can impact real-time interventional guidance and longitudinal vascular diagnostics and enable a next level of discovery based on quantitative observations in humans, within the novel requirements of precision and personalized medicine. PREMSOT considers the next steps in the MSOT development and will ❶ design and develop label-free portable hybrid MSOT and ultrasound imaging (US) for human use, ❷ research novel theory and hardware to address remaining MSOT limitations and improve the sensitivity and quantification accuracy, a necessary step for improving MSOT precision, ❸ i) validate quantitative MSOT imaging of tissue oxygenation and hypoxia, (micro)-vascular morphology and function, ii) research label-free imaging of inflammation and metabolism and iii) relate MSOT contrast to tissue and disease pathophysiology metrics and ❹ introduce label-free MSOT/US to discovery and clinical care. MSOT contrast features will be investigated as biomarkers in vascular medicine and surgery and in exploratory measurements within neurology, ambulatory/bedside care or sepsis, addressing unmet discovery and clinical needs.
Summary
The 2008 ERC Advanced Grant multispectral optoacoustic tomography (MSOT) yielded a novel modality for post-genomic small animal optical imaging, >110 peer-reviewed publications and several major awards including the 2014 Germany’s Innovation award. Since 2011 spin-off iThera Medical GmbH commercialized and placed MSOT systems in European, Asian and North American laboratories, making MSOT an international term. MSOT brought unprecedented optical imaging performance now enabling independent discovery and publications from researchers throughout the world.
Compared to other imaging modalities, MSOT uniquely images tissue oxygenation and other vascular and pathophysiology parameters in label-free and portable mode, using safe non-ionizing energy. Therefore, MSOT can impact real-time interventional guidance and longitudinal vascular diagnostics and enable a next level of discovery based on quantitative observations in humans, within the novel requirements of precision and personalized medicine. PREMSOT considers the next steps in the MSOT development and will ❶ design and develop label-free portable hybrid MSOT and ultrasound imaging (US) for human use, ❷ research novel theory and hardware to address remaining MSOT limitations and improve the sensitivity and quantification accuracy, a necessary step for improving MSOT precision, ❸ i) validate quantitative MSOT imaging of tissue oxygenation and hypoxia, (micro)-vascular morphology and function, ii) research label-free imaging of inflammation and metabolism and iii) relate MSOT contrast to tissue and disease pathophysiology metrics and ❹ introduce label-free MSOT/US to discovery and clinical care. MSOT contrast features will be investigated as biomarkers in vascular medicine and surgery and in exploratory measurements within neurology, ambulatory/bedside care or sepsis, addressing unmet discovery and clinical needs.
Max ERC Funding
2 497 268 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym PrenatStressAging
Project Prenatal Stress and Programming of Newborn and Infant Telomere Biology and Cellular Aging
Researcher (PI) Sonja Entringer
Host Institution (HI) CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary The long-term consequences of exposure to excess stress on the initiation and progression of many age-related diseases are well established. The period of intrauterine life represents among the most sensitive developmental windows, at which time the effects of stress may be transmitted inter-generationally from a mother to her as-yet-unborn child. The elucidation of mechanisms underlying such effects is an area of intense interest and investigation. Aging, by definition, occurs with advancing age, and age-related disorders result from exposures over the life span of factors that produce and accumulate damage. The novel concept advanced in this proposal is that the establishment of the integrity of key cellular aging-related processes that determine variation across individuals in the onset and progression of age-related disorders may originate very early in life (in utero) and may be plastic and influenced by developmental conditions. We propose that telomere biology and the epigenetic DNA methylation-based aging profile (DNAmAGE) represent candidate outcomes of particular interest in this context. A prospective, longitudinal cohort study of 350 mother-child dyads will be conducted from early pregnancy through birth till one year of age. Specific hypotheses about the effects of maternal stress and maternal-placental-fetal stress biology on newborn and infant telomere length, telomerase expression capacity, and DNAmAGE will be addressed. Serial measures of maternal psychological, behavioral and physiological characteristics will be collected across gestation using an innovative ecological momentary assessment (EMA) based real-time, ambulatory sampling protocol. The proposed study will help identify new strategies for risk identification and primary and secondary interventions to augment current efforts to prevent, delay and ameliorate age-related disorders.
Summary
The long-term consequences of exposure to excess stress on the initiation and progression of many age-related diseases are well established. The period of intrauterine life represents among the most sensitive developmental windows, at which time the effects of stress may be transmitted inter-generationally from a mother to her as-yet-unborn child. The elucidation of mechanisms underlying such effects is an area of intense interest and investigation. Aging, by definition, occurs with advancing age, and age-related disorders result from exposures over the life span of factors that produce and accumulate damage. The novel concept advanced in this proposal is that the establishment of the integrity of key cellular aging-related processes that determine variation across individuals in the onset and progression of age-related disorders may originate very early in life (in utero) and may be plastic and influenced by developmental conditions. We propose that telomere biology and the epigenetic DNA methylation-based aging profile (DNAmAGE) represent candidate outcomes of particular interest in this context. A prospective, longitudinal cohort study of 350 mother-child dyads will be conducted from early pregnancy through birth till one year of age. Specific hypotheses about the effects of maternal stress and maternal-placental-fetal stress biology on newborn and infant telomere length, telomerase expression capacity, and DNAmAGE will be addressed. Serial measures of maternal psychological, behavioral and physiological characteristics will be collected across gestation using an innovative ecological momentary assessment (EMA) based real-time, ambulatory sampling protocol. The proposed study will help identify new strategies for risk identification and primary and secondary interventions to augment current efforts to prevent, delay and ameliorate age-related disorders.
Max ERC Funding
1 483 720 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym ProFatMRI
Project Magnetic resonance imaging platform for probing fat microstructure
Researcher (PI) Dimitrios Karampinos
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Metabolic syndrome and osteoporosis are the two metabolic diseases with the highest and most rapidly growing prevalence, transforming them into a major global health and socioeconomic concern. Metabolic syndrome can be diagnosed with established biomarkers, but the selection of optimal prevention strategies for each individual patient is still problematic. Osteoporosis can be treated, but its current early diagnosis remains insufficient. The two diseases have been linked through the role of fat. Fat is central to their incidence and progression, and the probing of fat cellular properties can provide groundbreaking solutions for overcoming the existing challenges in the diseases early diagnosis and prevention.
In metabolic syndrome, there is evidence supporting a role of brown fat in preventing the disease. Brown fat has different microstructure than white fat. However, there is no established non-invasive biomarker to measure brown fat. In osteoporosis, there is evidence supporting a role of marrow fat, in combination with bone mineral density, for monitoring fracture risk. However, there is no non-invasive biomarker to measure marrow fat cellular changes in osteoporosis.
Magnetic resonance imaging (MRI) is the ideal modality for non-invasively measuring fat throughout the body. In order to differentiate brown from white fat and characterize the relationship between bone mineral and marrow fat cells, the employed MR methodology needs a technical breakthrough, shifting from the state-of-the-art water-centered paradigm to a fat-centered microstructural MRI paradigm. ProFatMRI describes an innovative research program that aims to develop and ex vivo validate diffusion and susceptibility MRI biomarkers of fat microstructure, and in vivo apply them at clinical MRI systems.
The resulting technologies will provide novel ways for selecting optimal individualized prevention strategies in metabolic syndrome and for achieving reliable risk fracture prediction in osteoporosis.
Summary
Metabolic syndrome and osteoporosis are the two metabolic diseases with the highest and most rapidly growing prevalence, transforming them into a major global health and socioeconomic concern. Metabolic syndrome can be diagnosed with established biomarkers, but the selection of optimal prevention strategies for each individual patient is still problematic. Osteoporosis can be treated, but its current early diagnosis remains insufficient. The two diseases have been linked through the role of fat. Fat is central to their incidence and progression, and the probing of fat cellular properties can provide groundbreaking solutions for overcoming the existing challenges in the diseases early diagnosis and prevention.
In metabolic syndrome, there is evidence supporting a role of brown fat in preventing the disease. Brown fat has different microstructure than white fat. However, there is no established non-invasive biomarker to measure brown fat. In osteoporosis, there is evidence supporting a role of marrow fat, in combination with bone mineral density, for monitoring fracture risk. However, there is no non-invasive biomarker to measure marrow fat cellular changes in osteoporosis.
Magnetic resonance imaging (MRI) is the ideal modality for non-invasively measuring fat throughout the body. In order to differentiate brown from white fat and characterize the relationship between bone mineral and marrow fat cells, the employed MR methodology needs a technical breakthrough, shifting from the state-of-the-art water-centered paradigm to a fat-centered microstructural MRI paradigm. ProFatMRI describes an innovative research program that aims to develop and ex vivo validate diffusion and susceptibility MRI biomarkers of fat microstructure, and in vivo apply them at clinical MRI systems.
The resulting technologies will provide novel ways for selecting optimal individualized prevention strategies in metabolic syndrome and for achieving reliable risk fracture prediction in osteoporosis.
Max ERC Funding
1 499 566 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym PROMETHEUS
Project Novel Cells for Organ Repair
Researcher (PI) Hans Schoeler
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Advanced Grant (AdG), LS7, ERC-2014-ADG
Summary In adult organisms, the natural ability to regenerate tissues damaged by injury or aging resides in multipotent tissue-specific precursors in local microenvironments. The number of these precursors is often either limited or declines sharply with age. Moreover, long-term adverse side effects of cancer treatments affect patients of any age. Such treatments tend to diminish the stem cell and progenitor cell populations.
In mammals pluripotency occurs only in the early embryo. Since 2006 it has been possible to turn ordinary somatic cells into pluripotent stem cells by using transcription factors (cellular reprogramming). However, pluripotency bears a risk for tumor formation, and thus conventional reprogramming strategies face the challenge of managing uncontrolled growth when applied to organs and tissues.
I propose to replenish the tissue-specific precursor cell pool by directly programming local somatic cell types into relevant precursors. My team has already generated such precursor cell types in vitro but not yet in vivo. To bridge the so far insurmountable gap between current in vitro and future in vivo use, we need innovative strategies. I propose to utilize the emerging field of organoid technology (small cell clusters of self-organized tissue) in a scalable automated system to screen possible factors for converting somatic cells into tissue-resident precursors and evaluate them in vivo.
This high-risk, high-gain approach enables the development of a new method for testing reprogramming strategies in 3D tissues. Our work indicates that somatic cells can be programmed to become multipotent somatic precursor cells with an efficiency above 50%. My approach circumvents the generation of a pluripotent state and its inherent tumor forming potential. It provides essential insights into the underlying cellular mechanisms of stem cell and tissue renewal in the natural niches and offers the potential of these somatic precursors to regenerate injured or aged tissues.
Summary
In adult organisms, the natural ability to regenerate tissues damaged by injury or aging resides in multipotent tissue-specific precursors in local microenvironments. The number of these precursors is often either limited or declines sharply with age. Moreover, long-term adverse side effects of cancer treatments affect patients of any age. Such treatments tend to diminish the stem cell and progenitor cell populations.
In mammals pluripotency occurs only in the early embryo. Since 2006 it has been possible to turn ordinary somatic cells into pluripotent stem cells by using transcription factors (cellular reprogramming). However, pluripotency bears a risk for tumor formation, and thus conventional reprogramming strategies face the challenge of managing uncontrolled growth when applied to organs and tissues.
I propose to replenish the tissue-specific precursor cell pool by directly programming local somatic cell types into relevant precursors. My team has already generated such precursor cell types in vitro but not yet in vivo. To bridge the so far insurmountable gap between current in vitro and future in vivo use, we need innovative strategies. I propose to utilize the emerging field of organoid technology (small cell clusters of self-organized tissue) in a scalable automated system to screen possible factors for converting somatic cells into tissue-resident precursors and evaluate them in vivo.
This high-risk, high-gain approach enables the development of a new method for testing reprogramming strategies in 3D tissues. Our work indicates that somatic cells can be programmed to become multipotent somatic precursor cells with an efficiency above 50%. My approach circumvents the generation of a pluripotent state and its inherent tumor forming potential. It provides essential insights into the underlying cellular mechanisms of stem cell and tissue renewal in the natural niches and offers the potential of these somatic precursors to regenerate injured or aged tissues.
Max ERC Funding
2 500 000 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
Project acronym ProstOmics
Project 'Tissue is the issue': a multi-omics approach to improve prostate cancer diagnosis
Researcher (PI) May-Britt Tessem
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary Overtreatment in prostate cancer (PCa) is a burden for health care economy and for quality of life. Correct diagnosis of early stage PCa is challenging given the limitations of the currently available clinical tools and the biological understanding of PCa. In this inter-disciplinary project, I propose an innovative approach enabling several cutting-edge ‘omics’ technologies (spatial metabolomics, genomics, transcriptomics) as well as histopathology to be performed on the same tissue sample. My goal is to reveal the molecular mechanisms of novel, but also promising metabolite biomarkers (citrate, polyamines, succinate and zinc) and their connection to recurrence, tissue heterogeneity and immune responses in complex human tissues. Such markers can personalize PCa diagnosis, open up new treatment strategies and fundamentally change the view of how to analyze tissue samples in the future. Furthermore, I want to demonstrate that citrate and polyamines are reliable prognostic markers that can be analyzed both in tissue and in patients in vivo by MR spectroscopic imaging. This work is made possible by the availability of high-quality fresh frozen tissue biobanks of prostatectomy biopsies with 5-10 years of follow-up data (N=1000)/slices (N=1000) and targeted in vivo snap-shot biopsies from clinical MR guided procedures (N=100). Among other techniques, I will implement high speed MALDI imaging (RapifleX MALDI TissueTyper) to the multi-omics protocol to study the spatial distribution and provide high resolution metabolic maps for each cell type, and which can be matched to both histopathology and MR Imaging. Multi-disciplinary platforms on large cohorts are needed to explore the clinical potential of the suggested molecular mechanisms. I expect that this ambitious proposal will address the diagnostic challenges of PCa and will further inspire the clinic and scientific community to follow the multi-omics approach within diagnosis and cancer research.
Summary
Overtreatment in prostate cancer (PCa) is a burden for health care economy and for quality of life. Correct diagnosis of early stage PCa is challenging given the limitations of the currently available clinical tools and the biological understanding of PCa. In this inter-disciplinary project, I propose an innovative approach enabling several cutting-edge ‘omics’ technologies (spatial metabolomics, genomics, transcriptomics) as well as histopathology to be performed on the same tissue sample. My goal is to reveal the molecular mechanisms of novel, but also promising metabolite biomarkers (citrate, polyamines, succinate and zinc) and their connection to recurrence, tissue heterogeneity and immune responses in complex human tissues. Such markers can personalize PCa diagnosis, open up new treatment strategies and fundamentally change the view of how to analyze tissue samples in the future. Furthermore, I want to demonstrate that citrate and polyamines are reliable prognostic markers that can be analyzed both in tissue and in patients in vivo by MR spectroscopic imaging. This work is made possible by the availability of high-quality fresh frozen tissue biobanks of prostatectomy biopsies with 5-10 years of follow-up data (N=1000)/slices (N=1000) and targeted in vivo snap-shot biopsies from clinical MR guided procedures (N=100). Among other techniques, I will implement high speed MALDI imaging (RapifleX MALDI TissueTyper) to the multi-omics protocol to study the spatial distribution and provide high resolution metabolic maps for each cell type, and which can be matched to both histopathology and MR Imaging. Multi-disciplinary platforms on large cohorts are needed to explore the clinical potential of the suggested molecular mechanisms. I expect that this ambitious proposal will address the diagnostic challenges of PCa and will further inspire the clinic and scientific community to follow the multi-omics approach within diagnosis and cancer research.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym RANGEMRI
Project Rapid Adaptive Nonlinear Gradient Encoding for Magnetic Resonance Imaging
Researcher (PI) Maxim Zaitsev
Host Institution (HI) UNIVERSITAETSKLINIKUM FREIBURG
Call Details Starting Grant (StG), LS7, ERC-2011-StG_20101109
Summary The project is aimed at the development of novel approaches for flexible signal localisation and encoding in Magnetic Resonance Imaging (MRI) for applications in neuroscience, neurology, oncology and further areas. The Rapid Adaptive Nonlinear Gradient Encoding for Magnetic Resonance Imaging (RANGE) methodology is based on the concept of applying localised, generally nonlinear encoding fields to faster, customised and anatomically-aligned imaging. The increase in encoding efficiency originates from several key factors: (i) local fields can be tailored to reduce peripheral nerve stimulation and power requirements to allow for faster switching; (ii) localised character of the fields requires less encoding steps and (iii) ability to select curved anatomy-adapted regions allows to cover target volumes with less slices; (iv) local encoding along curved surfaces reduces partial volume effects, delivering data of identical quality with lower nominal resolution compared to a standard approach. Each of these aspects is expected to contribute a factor of at least 2 to 3, resulting in a total encoding efficiency boost of an order of magnitude. Flexible fields will also be used for very high order localised dynamic shimming, allowing to further increase acquired data quality.
The technological backbone for the RANGE principle will be provided by a novel highly-integrated switchable matrix gradient coil. The new coil type will be able to generate both local nonlinear and global linear fields. Upon proper industrial realisation it is expected to match or even outperform traditional linear gradient coils, while providing an ultimate flexibility in generating rapidly switched localised fields.
Hardware, methodology and operator interface to the scanning process will be developed to handle signal selection, localisation and encoding in curved nonlinear coordinates to streamline the application development and facilitate the transfer to clinical practice and neuroscientific research.
Summary
The project is aimed at the development of novel approaches for flexible signal localisation and encoding in Magnetic Resonance Imaging (MRI) for applications in neuroscience, neurology, oncology and further areas. The Rapid Adaptive Nonlinear Gradient Encoding for Magnetic Resonance Imaging (RANGE) methodology is based on the concept of applying localised, generally nonlinear encoding fields to faster, customised and anatomically-aligned imaging. The increase in encoding efficiency originates from several key factors: (i) local fields can be tailored to reduce peripheral nerve stimulation and power requirements to allow for faster switching; (ii) localised character of the fields requires less encoding steps and (iii) ability to select curved anatomy-adapted regions allows to cover target volumes with less slices; (iv) local encoding along curved surfaces reduces partial volume effects, delivering data of identical quality with lower nominal resolution compared to a standard approach. Each of these aspects is expected to contribute a factor of at least 2 to 3, resulting in a total encoding efficiency boost of an order of magnitude. Flexible fields will also be used for very high order localised dynamic shimming, allowing to further increase acquired data quality.
The technological backbone for the RANGE principle will be provided by a novel highly-integrated switchable matrix gradient coil. The new coil type will be able to generate both local nonlinear and global linear fields. Upon proper industrial realisation it is expected to match or even outperform traditional linear gradient coils, while providing an ultimate flexibility in generating rapidly switched localised fields.
Hardware, methodology and operator interface to the scanning process will be developed to handle signal selection, localisation and encoding in curved nonlinear coordinates to streamline the application development and facilitate the transfer to clinical practice and neuroscientific research.
Max ERC Funding
1 497 672 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym REGAIN
Project Retinal Gene Alteration in XLRP
Researcher (PI) Knut Stieger
Host Institution (HI) JUSTUS-LIEBIG-UNIVERSITAET GIESSEN
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary "In this project the applicant proposes to develop a treatment strategy for a devastating blinding disorder affecting photoreceptor function within the first decade of life, X-linked Retinitis pigmentosa (XLRP). No treatment option exists to date.
The proposed treatment strategy is based on the idea of inducing homology directed repair (HDR) of the mutation by promoting the exchange between the endogenous mutated chromosomal sequence and an exogenous repair DNA template at a double strand break (DSB) site in vivo. The treatment will be realized by co-delivery of endonucleases and the template DNA via adeno-associated virus (AAV) based gene transfer. However, This strategy has never been applied in the retina in vivo and therefore, several parameters are unknown, i.e. the average frequency of HDR in photoreceptors, whether DNA repair will take place through HDR or not, and the average length of the DNA conversion tract during HDR.
The project includes the following parts: 1. Establishing the HDR frequency in photoreceptors in vivo: it is planned to optimize the frequency by co-delivery of trophic factors for the stimulation of the cellular repair machinery. 2. Inducing a bias of repair events towards HDR: it is planned to use nickases that only cut one DNA strand or will edit the expression profile of sensor proteins in the repair pathway in vitro and in vivo. 3. Optimization of the DNA conversion tract length: the expression profiles of helicases and other repair proteins are edited in vitro and in vivo. 4. Treatment of the PRGR2793delA mouse model: The optimized treatment settings are identified in order to test them for functional and morphological rescue effects.
Results from this study will significantly advance the state of the art in targeted gene correction strategies in vivo and patients with XLRP and other hereditary disorders will potentially benefit from it through extrapolating the results for a broader application."
Summary
"In this project the applicant proposes to develop a treatment strategy for a devastating blinding disorder affecting photoreceptor function within the first decade of life, X-linked Retinitis pigmentosa (XLRP). No treatment option exists to date.
The proposed treatment strategy is based on the idea of inducing homology directed repair (HDR) of the mutation by promoting the exchange between the endogenous mutated chromosomal sequence and an exogenous repair DNA template at a double strand break (DSB) site in vivo. The treatment will be realized by co-delivery of endonucleases and the template DNA via adeno-associated virus (AAV) based gene transfer. However, This strategy has never been applied in the retina in vivo and therefore, several parameters are unknown, i.e. the average frequency of HDR in photoreceptors, whether DNA repair will take place through HDR or not, and the average length of the DNA conversion tract during HDR.
The project includes the following parts: 1. Establishing the HDR frequency in photoreceptors in vivo: it is planned to optimize the frequency by co-delivery of trophic factors for the stimulation of the cellular repair machinery. 2. Inducing a bias of repair events towards HDR: it is planned to use nickases that only cut one DNA strand or will edit the expression profile of sensor proteins in the repair pathway in vitro and in vivo. 3. Optimization of the DNA conversion tract length: the expression profiles of helicases and other repair proteins are edited in vitro and in vivo. 4. Treatment of the PRGR2793delA mouse model: The optimized treatment settings are identified in order to test them for functional and morphological rescue effects.
Results from this study will significantly advance the state of the art in targeted gene correction strategies in vivo and patients with XLRP and other hereditary disorders will potentially benefit from it through extrapolating the results for a broader application."
Max ERC Funding
1 471 840 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym RESISTOME
Project Towards an individualised therapy and prevention of multi-drug resistant disease
Researcher (PI) Susanne Häußler
Host Institution (HI) HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary In this proposal the PIs medical microbiology background and previous internationally acknowledged work on molecular persistence mechanism of the gram-negative bacterial pathogen Pseudomonas aeruginosa is exploited towards a novel approach that could change the current paradigm of antibiotic resistance testing. Emerging resistance towards antimicrobials marks this decade and the lack of new therapy options especially against gram-negative pathogens underscores the need for optimisation of current diagnostics, therapies and prevention of the spread of these organisms.
The overall objective of this proposal is to apply a multi-disciplinary approach that combines clinical microbiology, state-of-the-art research on molecular resistance mechanisms, next generation-sequencing and array technology to uncover all genetic determinants of antibiotic resistance and to apply research towards the development of innovative molecular diagnostic platforms for rapid detection of resistance in order to accomplish individualised infection control measures, to reduce morbidity and mortality of the patients and to significantly reduce health care costs. The project will be performed at the Helmholtz Centre for Infection Research in Braunschweig which harbors a vast scientific and instrumental infrastructure and is perfectly suited for this type of pioneer research. Molecular diagnostics does not only provide a fast prediction of resistance based on the bacteria´s genotype but when performed directly in patients specimens has promise to transform medical microbiological diagnostics.
Summary
In this proposal the PIs medical microbiology background and previous internationally acknowledged work on molecular persistence mechanism of the gram-negative bacterial pathogen Pseudomonas aeruginosa is exploited towards a novel approach that could change the current paradigm of antibiotic resistance testing. Emerging resistance towards antimicrobials marks this decade and the lack of new therapy options especially against gram-negative pathogens underscores the need for optimisation of current diagnostics, therapies and prevention of the spread of these organisms.
The overall objective of this proposal is to apply a multi-disciplinary approach that combines clinical microbiology, state-of-the-art research on molecular resistance mechanisms, next generation-sequencing and array technology to uncover all genetic determinants of antibiotic resistance and to apply research towards the development of innovative molecular diagnostic platforms for rapid detection of resistance in order to accomplish individualised infection control measures, to reduce morbidity and mortality of the patients and to significantly reduce health care costs. The project will be performed at the Helmholtz Centre for Infection Research in Braunschweig which harbors a vast scientific and instrumental infrastructure and is perfectly suited for this type of pioneer research. Molecular diagnostics does not only provide a fast prediction of resistance based on the bacteria´s genotype but when performed directly in patients specimens has promise to transform medical microbiological diagnostics.
Max ERC Funding
1 479 487 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym RespeCT
Project Respiratory Disease Screening with Dark-Field Computed Tomography
Researcher (PI) Franz PFEIFFER
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS7, ERC-2015-AdG
Summary The grand goal of this proposal is to translate a recently explored and fundamentally different x-ray contrast mechanism, namely x-ray dark-field imaging, from present in-vivo small-animal proof-of-principle studies to a first clinical dark-field computed tomography (CT) prototype for future human diagnostics. Complementing this main technological development goal, we will explore the potential future clinical diagnostic application range of this technology by systematically screening multiple small-animal disease models.
As one of the potentially most beneficial applications, we will particularly focus on one rapidly growing challenge in the healthcare sector, namely the early detection and screening of chronic obstructive pulmonary disease (COPD). For Europe, COPD has been estimated to affect 5-10% of adults over 40 years of age. This translates to 12-25 million individuals affected by COPD in the European Union. If dark-field CT imaging can substantially improve early diagnosis and thus prompt appropriate therapeutic treatment in these patients, this project has the potential to prolong and improve the lives of millions of Europeans. Further, the cost of COPD to society in Europe could be decreased by billions each year, if COPD – with emphysema as one of its main components – could be accurately detected, effectively treated, and stabilized at early stages of the disease.
Besides COPD, we will explore the potential clinical benefit of dark-field CT for better diagnosis of pulmonary fibrosis, lung cancer, asthma, pneumothorax, acute lung injury, bronchopulmonary dysplasia, inflammation, and radiation-induced lung injury as a consequence of radiation therapy after lung cancer.
The ambition to deliver more than just an academic proof-of-principle development, but a clinically usable new imaging device for a broad medical community is underlined by a firm commitment of an industrial partner (Philips) to support this project, should the proposal receive funding.
Summary
The grand goal of this proposal is to translate a recently explored and fundamentally different x-ray contrast mechanism, namely x-ray dark-field imaging, from present in-vivo small-animal proof-of-principle studies to a first clinical dark-field computed tomography (CT) prototype for future human diagnostics. Complementing this main technological development goal, we will explore the potential future clinical diagnostic application range of this technology by systematically screening multiple small-animal disease models.
As one of the potentially most beneficial applications, we will particularly focus on one rapidly growing challenge in the healthcare sector, namely the early detection and screening of chronic obstructive pulmonary disease (COPD). For Europe, COPD has been estimated to affect 5-10% of adults over 40 years of age. This translates to 12-25 million individuals affected by COPD in the European Union. If dark-field CT imaging can substantially improve early diagnosis and thus prompt appropriate therapeutic treatment in these patients, this project has the potential to prolong and improve the lives of millions of Europeans. Further, the cost of COPD to society in Europe could be decreased by billions each year, if COPD – with emphysema as one of its main components – could be accurately detected, effectively treated, and stabilized at early stages of the disease.
Besides COPD, we will explore the potential clinical benefit of dark-field CT for better diagnosis of pulmonary fibrosis, lung cancer, asthma, pneumothorax, acute lung injury, bronchopulmonary dysplasia, inflammation, and radiation-induced lung injury as a consequence of radiation therapy after lung cancer.
The ambition to deliver more than just an academic proof-of-principle development, but a clinically usable new imaging device for a broad medical community is underlined by a firm commitment of an industrial partner (Philips) to support this project, should the proposal receive funding.
Max ERC Funding
2 357 213 €
Duration
Start date: 2016-08-01, End date: 2021-07-31
Project acronym SELECTIONPREDISPOSED
Project Novel Tools for Early Childhood Predisposition to Obesity
Researcher (PI) Pål Rasmus Njølstad
Host Institution (HI) UNIVERSITETET I BERGEN
Call Details Advanced Grant (AdG), LS7, ERC-2011-ADG_20110310
Summary An estimated 22 million children worldwide under age five are overweight. In these children, obesity is a primary indicator for development of type 2 diabetes and possibly cancer. I present a research program, SELECTionPREDISPOSED, to identify novel obesity-risk genes as tools for detection of early childhood obesity making possible a selective prevention program in predisposed children. I will use records and blood samples from children and their parents in the Mother-Child Cohort of Norway, the Health Survey of Nord-Trøndelag and the Norwegian Birth Registry and cross-correlate the databases for genetic research. I hypothesize that children large at birth with enhanced infantile growth may be predisposed to obesity by genetic factors. Obesity-linked genes are likely to include a mix of variants associated with glucose, insulin and fat metabolism and may be identifiable in population studies using biobanks and end-point registries. The state-of-the-art approach is to identify diabetes- or obesity-associated genes in subjects with disease. My approach is to investigate subsets of children with high and low birth weights and BMIs at age six. Using cutting-edge genetic techniques like GWAS, copy-number variation and massive parallel exome and epigenome sequencing I will correlate the genetic information with clinical data in large national end-point registries by a case-control design subsequent replication in large data sets and control for environmental confounders by cross-correlation to the national birth registry. I want to change the field by working with predisposed children in order to influence the ratio between those that may and may not develop obesity and diabetes. In this way my team will develop contextual tools of a groundbreaking nature. This “tool-kit” may make it possible to identify and implement in predisposed children, an early low-cost prevention program to slow down and reverse the development of obesity and prevent diabetes and possibly cancer.
Summary
An estimated 22 million children worldwide under age five are overweight. In these children, obesity is a primary indicator for development of type 2 diabetes and possibly cancer. I present a research program, SELECTionPREDISPOSED, to identify novel obesity-risk genes as tools for detection of early childhood obesity making possible a selective prevention program in predisposed children. I will use records and blood samples from children and their parents in the Mother-Child Cohort of Norway, the Health Survey of Nord-Trøndelag and the Norwegian Birth Registry and cross-correlate the databases for genetic research. I hypothesize that children large at birth with enhanced infantile growth may be predisposed to obesity by genetic factors. Obesity-linked genes are likely to include a mix of variants associated with glucose, insulin and fat metabolism and may be identifiable in population studies using biobanks and end-point registries. The state-of-the-art approach is to identify diabetes- or obesity-associated genes in subjects with disease. My approach is to investigate subsets of children with high and low birth weights and BMIs at age six. Using cutting-edge genetic techniques like GWAS, copy-number variation and massive parallel exome and epigenome sequencing I will correlate the genetic information with clinical data in large national end-point registries by a case-control design subsequent replication in large data sets and control for environmental confounders by cross-correlation to the national birth registry. I want to change the field by working with predisposed children in order to influence the ratio between those that may and may not develop obesity and diabetes. In this way my team will develop contextual tools of a groundbreaking nature. This “tool-kit” may make it possible to identify and implement in predisposed children, an early low-cost prevention program to slow down and reverse the development of obesity and prevent diabetes and possibly cancer.
Max ERC Funding
2 299 549 €
Duration
Start date: 2012-09-01, End date: 2018-08-31
Project acronym SIRMIO
Project Small animal proton Irradiator for Research in Molecular Image-guided radiation-Oncology
Researcher (PI) Katia PARODI
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary Precision small animal radiotherapy (RT) research is a young emerging field aiming at unravelling complex in-vivo mechanisms of radiation damage in target and non-target tissues, for translation into improved clinical treatment strategies.
For commonly used X-rays, commercial small animal radiation research platforms were recently developed to provide precision imaged-guided RT comparable to state-of-the-art human treatment. Conversely, such platforms are not yet existing for proton beams, which are increasingly used in RT due to their superior ability to concentrate beam energy in the tumour and spare normal tissue. Pre-clinical research is thus carried out at the few available proton therapy facilities, lacking adequate beam quality and image-guidance for small animal treatment.
To fill this gap, this project will realize and demonstrate the first prototype system for precision small animal proton irradiation at existing experimental beamlines of clinical facilities. Improved beam quality for targeting small structures will be achieved via a dedicated magnetic focusing system. Innovative in-situ image-guidance will combine ion-specific solutions of proton-transmission imaging (for treatment planning) and thermoacoustics (for verification of the beam range) with established ultrasound (for real-time morphological confirmation) and positron-emission-tomography (for functional assessment). The resulting multi-modal “sight” will be used to foster new workflows of treatment adaptation. The system will be thoroughly tested and finally deployed in a first in-vivo study in different orthotopic mouse cancer models, in comparison to reference X-ray RT at a commercial small animal platform.
SIRMIO will deliver the first, compact and cost-effective precision small animal proton irradiator for advancing molecular oncology and animal-based proton RT research, thereby providing new experimental insights in biological in-situ responses towards proton and photon irradiation.
Summary
Precision small animal radiotherapy (RT) research is a young emerging field aiming at unravelling complex in-vivo mechanisms of radiation damage in target and non-target tissues, for translation into improved clinical treatment strategies.
For commonly used X-rays, commercial small animal radiation research platforms were recently developed to provide precision imaged-guided RT comparable to state-of-the-art human treatment. Conversely, such platforms are not yet existing for proton beams, which are increasingly used in RT due to their superior ability to concentrate beam energy in the tumour and spare normal tissue. Pre-clinical research is thus carried out at the few available proton therapy facilities, lacking adequate beam quality and image-guidance for small animal treatment.
To fill this gap, this project will realize and demonstrate the first prototype system for precision small animal proton irradiation at existing experimental beamlines of clinical facilities. Improved beam quality for targeting small structures will be achieved via a dedicated magnetic focusing system. Innovative in-situ image-guidance will combine ion-specific solutions of proton-transmission imaging (for treatment planning) and thermoacoustics (for verification of the beam range) with established ultrasound (for real-time morphological confirmation) and positron-emission-tomography (for functional assessment). The resulting multi-modal “sight” will be used to foster new workflows of treatment adaptation. The system will be thoroughly tested and finally deployed in a first in-vivo study in different orthotopic mouse cancer models, in comparison to reference X-ray RT at a commercial small animal platform.
SIRMIO will deliver the first, compact and cost-effective precision small animal proton irradiator for advancing molecular oncology and animal-based proton RT research, thereby providing new experimental insights in biological in-situ responses towards proton and photon irradiation.
Max ERC Funding
1 525 925 €
Duration
Start date: 2017-11-01, End date: 2021-10-31
Project acronym STEMCHIP
Project Probing organ-level stem cell dynamics on a chip
Researcher (PI) Matthias Lutolf
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary "More than 30’000 patients with hematological malignancies greatly benefit from hematopoietic stem cell (HSC) transplants each year in Europe alone. However, availability of transplant material for afflicted patients, prognosis, and relapse-free survival are all hindered by the limited quantity of HSCs available for therapy. Despite several decades of research, HSC cannot be cultured in vitro without rapidly differentiating. This is largely due to our poor understanding of the mechanisms that regulate HSC fate in response to cues from their microenvironmental ‘niche’, and the difficulty to unveil these mechanisms using existing experimental model systems. Building on our extensive expertise in the engineering of artificial stem cell niches and microfluidic technology, here I propose to develop a novel in vitro bone marrow model to recapitulate its organ-level function in regulating HSC fate. A modular microfluidic system, termed ‘bone marrow-on-chip’, will be designed comprising a niche compartment, mimicking key anatomical, cellular and molecular characteristics of the HSC niche. This niche compartment will be coupled to a fluidic network, as a simplistic surrogate of the native circulation such as to inject and remove HSC progeny for various analyses. This should allow, for the first time, the in vitro modelling of dynamic physiological HSC processes such as the ‘homing’ of stem cells to the niche after transplantation, and the ‘mobilization’ of stem cells from the niche upon systemic stimulation. With this tool we will be able to gain insight into the cell types and factors found in HSC niches and how they influence HSC behavior in mice and humans, providing paths forward to designing novel HSC expansion procedures. The successful realization of this concept would represent a scientific and technological paradigm shift with impact beyond the field of hematopoiesis, opening up new horizons for the for the study of other stem cell and even tumor cell types."
Summary
"More than 30’000 patients with hematological malignancies greatly benefit from hematopoietic stem cell (HSC) transplants each year in Europe alone. However, availability of transplant material for afflicted patients, prognosis, and relapse-free survival are all hindered by the limited quantity of HSCs available for therapy. Despite several decades of research, HSC cannot be cultured in vitro without rapidly differentiating. This is largely due to our poor understanding of the mechanisms that regulate HSC fate in response to cues from their microenvironmental ‘niche’, and the difficulty to unveil these mechanisms using existing experimental model systems. Building on our extensive expertise in the engineering of artificial stem cell niches and microfluidic technology, here I propose to develop a novel in vitro bone marrow model to recapitulate its organ-level function in regulating HSC fate. A modular microfluidic system, termed ‘bone marrow-on-chip’, will be designed comprising a niche compartment, mimicking key anatomical, cellular and molecular characteristics of the HSC niche. This niche compartment will be coupled to a fluidic network, as a simplistic surrogate of the native circulation such as to inject and remove HSC progeny for various analyses. This should allow, for the first time, the in vitro modelling of dynamic physiological HSC processes such as the ‘homing’ of stem cells to the niche after transplantation, and the ‘mobilization’ of stem cells from the niche upon systemic stimulation. With this tool we will be able to gain insight into the cell types and factors found in HSC niches and how they influence HSC behavior in mice and humans, providing paths forward to designing novel HSC expansion procedures. The successful realization of this concept would represent a scientific and technological paradigm shift with impact beyond the field of hematopoiesis, opening up new horizons for the for the study of other stem cell and even tumor cell types."
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-12-01, End date: 2017-11-30
Project acronym StopAutoimmunity
Project Recurrent disease in the liver transplant: window to identify and stop gut signals driving autoimmunity
Researcher (PI) Johannes Espolin Roksund HOV
Host Institution (HI) UNIVERSITETET I OSLO
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Autoimmune disease is an increasing health concern. These diseases are strongly associated with altered gut microbiome. When immunosuppression fails there is little to offer in terms of therapy. In this project, I hypothesize that gut signals (microbial factors from the intestine) unaffected by immunosuppression are key drivers of autoimmune diseases. I propose to use recurrent autoimmune disease after organ transplantation as a human disease model to identify and stop these gut signals, providing a novel approach to close the gap between basic microbiome research and patient care in autoimmune diseases.
To identify autoimmunity-related gut signals, I will use patients with primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts. PSC is a common indication for liver transplantation, but after transplantation there is high risk of recurrent PSC (rPSC). I recently showed that the PSC gut microbiome has low diversity and identified microbial metabolites associated with severe PSC. Preliminary data show that the post-transplant gut is even less diverse, suggesting that microbial factors drive autoimmunity.
In this project I will identify gut signals by in-depth investigation of gut bacterial genes and circulating metabolites in the blood. The outcome will be diagnostic and prognostic markers overlapping in PSC and rPSC, defined by changes in gut bacterial genes and concentrations of bacterial metabolites in the blood. Next, I will investigate if common drugs or interventions influence the identified autoimmunity-related gut signals. By generating a library of interventions influencing the gut microbiome it will be possible to select promising candidates for pilot treatment trials after liver transplantation.
The outcome of StopAutoimmunity will be gut signals useful as novel biomarkers and treatment targets. These may directly translate into improved patient care but also provide a foundation for understanding the mechanisms of autoimmunity.
Summary
Autoimmune disease is an increasing health concern. These diseases are strongly associated with altered gut microbiome. When immunosuppression fails there is little to offer in terms of therapy. In this project, I hypothesize that gut signals (microbial factors from the intestine) unaffected by immunosuppression are key drivers of autoimmune diseases. I propose to use recurrent autoimmune disease after organ transplantation as a human disease model to identify and stop these gut signals, providing a novel approach to close the gap between basic microbiome research and patient care in autoimmune diseases.
To identify autoimmunity-related gut signals, I will use patients with primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts. PSC is a common indication for liver transplantation, but after transplantation there is high risk of recurrent PSC (rPSC). I recently showed that the PSC gut microbiome has low diversity and identified microbial metabolites associated with severe PSC. Preliminary data show that the post-transplant gut is even less diverse, suggesting that microbial factors drive autoimmunity.
In this project I will identify gut signals by in-depth investigation of gut bacterial genes and circulating metabolites in the blood. The outcome will be diagnostic and prognostic markers overlapping in PSC and rPSC, defined by changes in gut bacterial genes and concentrations of bacterial metabolites in the blood. Next, I will investigate if common drugs or interventions influence the identified autoimmunity-related gut signals. By generating a library of interventions influencing the gut microbiome it will be possible to select promising candidates for pilot treatment trials after liver transplantation.
The outcome of StopAutoimmunity will be gut signals useful as novel biomarkers and treatment targets. These may directly translate into improved patient care but also provide a foundation for understanding the mechanisms of autoimmunity.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym STRATO
Project Stress as a modifier of atherosclerosis - Novel mechanistic insights and therapeutic avenues -
Researcher (PI) Hendrik SAGER
Host Institution (HI) DEUTSCHES HERZZENTRUM MUNCHEN
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary Atherosclerosis and its complications such as acute coronary syndromes (myocardial infarction and unstable angina) are leading causes of death in the EU and worldwide. Mental stress is known to be a major trigger for the onset of acute coronary syndromes, even in patients with state-of-the-art medical treatment. How acute mental stress rapidly drives plaque destabilization causing acute coronary syndromes is poorly understood and consequently specific treatment, although urgently needed, is lacking. Mental stress is known to affect the immune system. Leukocytes, the effector cells of the immune system, are main instigators not only of plaque progression, but also of plaque destabilization. We hypothesize that acute mental stress rapidly aggravates plaque inflammation, which renders plaques more vulnerable and prone to rupture.
We aim to characterize the impact of stress on plaque inflammation in a mouse model of acute mental stress. We will explore the mechanisms by which acute mental stress drives plaque inflammation. Based on these findings, we aim to provide a novel treatment approach to mitigate stress exacerbated plaque inflammation. Further, we aim to translate our findings to stressed humans.
The STRATO study will be carried out in a multidisciplinary approach including basic and clinician scientists, immunologists, and psychosomatic specialists and will provide us with an unprecedented, comprehensive picture of how acute mental stress aggravates atherosclerosis. Our study will fill a gap in mechanistic knowledge and based on this will identify novel therapeutic measures with the aim to reduce acute mental stress related cardiovascular complications.
Summary
Atherosclerosis and its complications such as acute coronary syndromes (myocardial infarction and unstable angina) are leading causes of death in the EU and worldwide. Mental stress is known to be a major trigger for the onset of acute coronary syndromes, even in patients with state-of-the-art medical treatment. How acute mental stress rapidly drives plaque destabilization causing acute coronary syndromes is poorly understood and consequently specific treatment, although urgently needed, is lacking. Mental stress is known to affect the immune system. Leukocytes, the effector cells of the immune system, are main instigators not only of plaque progression, but also of plaque destabilization. We hypothesize that acute mental stress rapidly aggravates plaque inflammation, which renders plaques more vulnerable and prone to rupture.
We aim to characterize the impact of stress on plaque inflammation in a mouse model of acute mental stress. We will explore the mechanisms by which acute mental stress drives plaque inflammation. Based on these findings, we aim to provide a novel treatment approach to mitigate stress exacerbated plaque inflammation. Further, we aim to translate our findings to stressed humans.
The STRATO study will be carried out in a multidisciplinary approach including basic and clinician scientists, immunologists, and psychosomatic specialists and will provide us with an unprecedented, comprehensive picture of how acute mental stress aggravates atherosclerosis. Our study will fill a gap in mechanistic knowledge and based on this will identify novel therapeutic measures with the aim to reduce acute mental stress related cardiovascular complications.
Max ERC Funding
1 477 680 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym SUMMIT
Project Stepping Up mRNA Mutanome Immunotherapy
Researcher (PI) Ugur SAHIN
Host Institution (HI) TRON - TRANSLATIONALE ONKOLOGIE ANDER UNIVERSITATSMEDIZIN DER JOHANNES GUTENBERG-UNIVERSITAT MAINZ GEMEINNUTZIGE GMBH
Call Details Advanced Grant (AdG), LS7, ERC-2017-ADG
Summary Immunotherapy is expected to fundamentally change the treatment of cancer patients. Personalized vaccines eliciting
immune responses against individual cancer mutations have moved into the spotlight. We have pioneered the field and
moved ´cancer mutanome vaccines´ from a mere vision into a disruptive medical concept compatible with current
standards of drug development and health care practice. Solving key scientific and technological challenges and building
on extensive preclinical studies, we showed in a first-in-human trial potent tumor-directed immunity in every single
vaccinated patient, and clinical activity of a novel mRNA-based mutanome vaccine. Given that mutations are a hallmark
of cancer, mRNA mutanome vaccines are universal drugs the efficacy of which are unaffected by the cancer type. The
aim of this proposal is to ignite the next wave of advancement by addressing four key constraints challenging a full clinical
realization of such vaccines. We will address the scarcity of point mutations in many tumors by extending neoepitope
discovery to the full spectrum of genetic aberrations. Cancers are heterogeneous and outgrowth of clones unaccounted
for by the vaccine is an efficient escape mechanism. We will develop neoepitope prediction algorithms deciphering clonal
heterogeneity to inform rational vaccine design and countermeasures against selection of target escape variants. Tumor
cell resistance to vaccine-induced T cells due to antigen presentation defects will be addressed by developing strategies
for mobilizing the full repertoire of immune effector mechanisms, including antibodies and NK cells. T-cell exhaustion will
be tackled by vaccination protocols promoting long-lived memory responses and by combination treatments counteracting
tumor-mediated immunosuppression. Finally, we will drive the seamless clinical translation of the scientific findings by
close interdisciplinary collaboration with strong and established clinical and industrial partners.
Summary
Immunotherapy is expected to fundamentally change the treatment of cancer patients. Personalized vaccines eliciting
immune responses against individual cancer mutations have moved into the spotlight. We have pioneered the field and
moved ´cancer mutanome vaccines´ from a mere vision into a disruptive medical concept compatible with current
standards of drug development and health care practice. Solving key scientific and technological challenges and building
on extensive preclinical studies, we showed in a first-in-human trial potent tumor-directed immunity in every single
vaccinated patient, and clinical activity of a novel mRNA-based mutanome vaccine. Given that mutations are a hallmark
of cancer, mRNA mutanome vaccines are universal drugs the efficacy of which are unaffected by the cancer type. The
aim of this proposal is to ignite the next wave of advancement by addressing four key constraints challenging a full clinical
realization of such vaccines. We will address the scarcity of point mutations in many tumors by extending neoepitope
discovery to the full spectrum of genetic aberrations. Cancers are heterogeneous and outgrowth of clones unaccounted
for by the vaccine is an efficient escape mechanism. We will develop neoepitope prediction algorithms deciphering clonal
heterogeneity to inform rational vaccine design and countermeasures against selection of target escape variants. Tumor
cell resistance to vaccine-induced T cells due to antigen presentation defects will be addressed by developing strategies
for mobilizing the full repertoire of immune effector mechanisms, including antibodies and NK cells. T-cell exhaustion will
be tackled by vaccination protocols promoting long-lived memory responses and by combination treatments counteracting
tumor-mediated immunosuppression. Finally, we will drive the seamless clinical translation of the scientific findings by
close interdisciplinary collaboration with strong and established clinical and industrial partners.
Max ERC Funding
2 482 500 €
Duration
Start date: 2018-08-01, End date: 2023-07-31
Project acronym SYNAPLAST MR
Project Imaging synaptic plasticity by ultra-high field magnetic resonance spectroscopy in health and psychiatric disease
Researcher (PI) Anke Henning
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary A large number of psychiatric disorders (major and bipolar depression (MDD / BD), schizophrenia, obsessive-compulsive disorder (OCD), addiction, anxiety, attention deficit hyperactivity syndrome (ADHS), posttraumatic stress disorder (PTSD), autism) lack objective criteria for primary diagnosis, early differential diagnosis with regard to subtypes in treatment response and disease progression or effective therapy monitoring. Hence, the search for relevant biomarkers is of high importance. This proposal suggests the development of novel methodology for highly spatially and temporally resolved imaging of disease effects on neurotransmission, membrane processes related to synaptic plasticity and brain energy metabolism in psychiatric disorders and the acute and chronic impact of related pharmacological treatment in the human brain. To that, the advantages of a unique 9.4 T whole body human magnetic resonance imaging (MRI) system for 1H, 31P and 13C magnetic resonance spectroscopic imaging shall be exploited. Highly innovative enabling MRI technology including parallel transmission, very high order B0 shimming, a real time field stabilization and motion correction approach along with the principles of advanced encoding and non-Fourier image reconstruction shall ensure high data quality. Next to obtaining 20 novel image contrasts based on steady state metabolite concentrations, the ultimate goal of the proposed research is to enable functional spectroscopic imaging in the entire human brain in order to investigate adaptation of neurotransmission and brain metabolism to environmental stimuli as well as the impact of acute pharmacological intervention. Finally, the spatially and temporally resolved metabolic imaging technology shall be used for investigation of patients with major depressive disorder to reveal novel biomarkers relevant for diagnostics and patient stratification.
Summary
A large number of psychiatric disorders (major and bipolar depression (MDD / BD), schizophrenia, obsessive-compulsive disorder (OCD), addiction, anxiety, attention deficit hyperactivity syndrome (ADHS), posttraumatic stress disorder (PTSD), autism) lack objective criteria for primary diagnosis, early differential diagnosis with regard to subtypes in treatment response and disease progression or effective therapy monitoring. Hence, the search for relevant biomarkers is of high importance. This proposal suggests the development of novel methodology for highly spatially and temporally resolved imaging of disease effects on neurotransmission, membrane processes related to synaptic plasticity and brain energy metabolism in psychiatric disorders and the acute and chronic impact of related pharmacological treatment in the human brain. To that, the advantages of a unique 9.4 T whole body human magnetic resonance imaging (MRI) system for 1H, 31P and 13C magnetic resonance spectroscopic imaging shall be exploited. Highly innovative enabling MRI technology including parallel transmission, very high order B0 shimming, a real time field stabilization and motion correction approach along with the principles of advanced encoding and non-Fourier image reconstruction shall ensure high data quality. Next to obtaining 20 novel image contrasts based on steady state metabolite concentrations, the ultimate goal of the proposed research is to enable functional spectroscopic imaging in the entire human brain in order to investigate adaptation of neurotransmission and brain metabolism to environmental stimuli as well as the impact of acute pharmacological intervention. Finally, the spatially and temporally resolved metabolic imaging technology shall be used for investigation of patients with major depressive disorder to reveal novel biomarkers relevant for diagnostics and patient stratification.
Max ERC Funding
1 505 000 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym SYNVIA
Project Synthetic viability of homologous recombination-deficient cancers
Researcher (PI) Sven Rottenberg
Host Institution (HI) UNIVERSITAET BERN
Call Details Consolidator Grant (CoG), LS7, ERC-2015-CoG
Summary Although various effective anti-cancer drug treatments have become available over the last decades, drug resistance remains the major cause of death of cancer patients. Striking examples are patients with tumors that are defective in DNA repair by homologous recombination (HR). Despite initial responses to cancer therapy, resistance of primary or disseminated tumors eventually emerges, which minimizes therapeutic options and greatly reduces survival. The molecular mechanisms underlying this therapy escape are often poorly understood.
In the SYNVIA project I will address the problem of therapy escape by using powerful genetically engineered mouse models for BRCA1- and BRCA2-deficient breast cancer, which closely mimic the human disease. Due to the BRCA inactivation, the tumors that arise lack HR-directed DNA repair. Similar to the situation in cancer patients, we observe that cancer cells in these models eventually escape the deadly effects of chemotherapy or novel targeted drugs. Thus, these resistance models provide a unique opportunity to explore therapy escape mechanisms.
I propose an approach that will take the in vivo analysis of therapy resistance mechanisms to a new level. By synergizing the advantages of next generation sequencing with functional genetic screens in tractable model systems, I will explore novel mechanisms that cause resistance of HR-deficient cancers by the loss of another gene (“synthetic viability”). I provide evidence that new mechanisms of resistance can be identified with this approach. In an innovative step, I will generate genome-wide alterations using the revolutionizing CRISPR/Cas technology. Mutations will also be introduced into 3D tumor organoid cultures, as we found that these are more physiologically relevant. I am convinced that the combination of these state-of-the-art approaches will yield highly useful information for designing effective approaches to circumvent or reverse therapy escape in human cancer patients.
Summary
Although various effective anti-cancer drug treatments have become available over the last decades, drug resistance remains the major cause of death of cancer patients. Striking examples are patients with tumors that are defective in DNA repair by homologous recombination (HR). Despite initial responses to cancer therapy, resistance of primary or disseminated tumors eventually emerges, which minimizes therapeutic options and greatly reduces survival. The molecular mechanisms underlying this therapy escape are often poorly understood.
In the SYNVIA project I will address the problem of therapy escape by using powerful genetically engineered mouse models for BRCA1- and BRCA2-deficient breast cancer, which closely mimic the human disease. Due to the BRCA inactivation, the tumors that arise lack HR-directed DNA repair. Similar to the situation in cancer patients, we observe that cancer cells in these models eventually escape the deadly effects of chemotherapy or novel targeted drugs. Thus, these resistance models provide a unique opportunity to explore therapy escape mechanisms.
I propose an approach that will take the in vivo analysis of therapy resistance mechanisms to a new level. By synergizing the advantages of next generation sequencing with functional genetic screens in tractable model systems, I will explore novel mechanisms that cause resistance of HR-deficient cancers by the loss of another gene (“synthetic viability”). I provide evidence that new mechanisms of resistance can be identified with this approach. In an innovative step, I will generate genome-wide alterations using the revolutionizing CRISPR/Cas technology. Mutations will also be introduced into 3D tumor organoid cultures, as we found that these are more physiologically relevant. I am convinced that the combination of these state-of-the-art approaches will yield highly useful information for designing effective approaches to circumvent or reverse therapy escape in human cancer patients.
Max ERC Funding
1 999 438 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym TALE
Project Therapeutic Allele Engineering: A novel technology for cell therapy
Researcher (PI) Lukas JEKER
Host Institution (HI) UNIVERSITAT BASEL
Call Details Consolidator Grant (CoG), LS7, ERC-2018-COG
Summary We are currently witnessing a revolution in cell therapies that are routed in decades of basic research in genetics, cell biology and immunology. A deep understanding of mammalian, and in particular immune, cells is currently being translated into highly efficient cell-based therapeutics. Technologic breakthroughs in genetic and genome engineering are further fueling the generation of customized, high precision therapies that are based on cells as “smart drugs”. For instance, reprogramming immune killer cells to recognize B cell leukemias resulted in unprecedented clinical responses in treatment-resistant and relapsed patients. However, currently only very few, highly selected patients benefit from these developments. A fundamental problem of today’s cell therapies is that transferred cells cannot be distinguished from host cells. We have developed “allele engineering”, a new technology that solves this challenge. Here, we outline how allele engineering will improve the safety and efficacy of cell therapies. We will 1) generate a non-viral, DNA-free safety/shielding switch 2) develop a radically new curative approach to acute myeloid leukemia 3) rationally design a safe allele engineering solution for human therapy and 4) use allele engineering as a curative therapy of scurfy syndrome, a lethal monogenic autoimmune disease. Allele engineering enables completely new treatment strategies and can be applied to any surface protein. Therefore, I anticipate that the results will have a major impact on the field.
Summary
We are currently witnessing a revolution in cell therapies that are routed in decades of basic research in genetics, cell biology and immunology. A deep understanding of mammalian, and in particular immune, cells is currently being translated into highly efficient cell-based therapeutics. Technologic breakthroughs in genetic and genome engineering are further fueling the generation of customized, high precision therapies that are based on cells as “smart drugs”. For instance, reprogramming immune killer cells to recognize B cell leukemias resulted in unprecedented clinical responses in treatment-resistant and relapsed patients. However, currently only very few, highly selected patients benefit from these developments. A fundamental problem of today’s cell therapies is that transferred cells cannot be distinguished from host cells. We have developed “allele engineering”, a new technology that solves this challenge. Here, we outline how allele engineering will improve the safety and efficacy of cell therapies. We will 1) generate a non-viral, DNA-free safety/shielding switch 2) develop a radically new curative approach to acute myeloid leukemia 3) rationally design a safe allele engineering solution for human therapy and 4) use allele engineering as a curative therapy of scurfy syndrome, a lethal monogenic autoimmune disease. Allele engineering enables completely new treatment strategies and can be applied to any surface protein. Therefore, I anticipate that the results will have a major impact on the field.
Max ERC Funding
2 397 082 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym ThermalMR
Project Thermal Magnetic Resonance: A New Instrument to Define the Role of Temperature in Biological Systems and Disease for Diagnosis and Therapy
Researcher (PI) Thoralf Niendorf
Host Institution (HI) MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Temperature is a physical parameter with diverse biological implications and crucial clinical relevance. With an ever increasing interest in thermal applications, non-invasive in vivo methods to modulate temperature and characterize subsequent effects are imperative. Magnetic resonance (MR) is a mainstay of diagnosis but lacks inherent means for focal thermal modulation.
Ultrahigh field (UHF) MR employs higher radio frequencies (RF) than conventional MR and has unique potential to provide focal temperature manipulation and high resolution imaging (ThermalMR). Our simulations show that we can adapt an UHF- MR device to generate heat in highly focused regions of tissue by using high-density RF transmitter arrays. This new instrument will provide a revolutionary method for precise in vivo temperature manipulations. To establish high-fidelity thermal dosimetry, we will investigate pioneering strategies that exploit electrical and heat transfer tissue properties. For thermal dosage control, novel methods of MR thermometry will be developed. The capacity of ThermalMR for thermal intervention will be demonstrated in model systems. Its efficacy for drug release will be explored using new thermo-responsive nanocarriers loaded with fluorinated probes, exquisitely quantifiable with 19F MR. The applicability and safety of ThermalMR will be demonstrated in animal models followed by a feasibility study in healthy subjects. To link thermal responses of MR contrasts with molecular signatures, gene expression profiling will be performed. The aim is to understand the thermal properties of healthy and pathological tissues and explore the use of temperature modulation as a therapeutic tool. ThermalMR will eradicate the main barriers to the study and use of temperature - a critical dimension of life that is of intense clinical interest, but so far very poorly understood. This approach opens an entirely new research field of thermal phenotyping: where physics, biology and medicine meet.
Summary
Temperature is a physical parameter with diverse biological implications and crucial clinical relevance. With an ever increasing interest in thermal applications, non-invasive in vivo methods to modulate temperature and characterize subsequent effects are imperative. Magnetic resonance (MR) is a mainstay of diagnosis but lacks inherent means for focal thermal modulation.
Ultrahigh field (UHF) MR employs higher radio frequencies (RF) than conventional MR and has unique potential to provide focal temperature manipulation and high resolution imaging (ThermalMR). Our simulations show that we can adapt an UHF- MR device to generate heat in highly focused regions of tissue by using high-density RF transmitter arrays. This new instrument will provide a revolutionary method for precise in vivo temperature manipulations. To establish high-fidelity thermal dosimetry, we will investigate pioneering strategies that exploit electrical and heat transfer tissue properties. For thermal dosage control, novel methods of MR thermometry will be developed. The capacity of ThermalMR for thermal intervention will be demonstrated in model systems. Its efficacy for drug release will be explored using new thermo-responsive nanocarriers loaded with fluorinated probes, exquisitely quantifiable with 19F MR. The applicability and safety of ThermalMR will be demonstrated in animal models followed by a feasibility study in healthy subjects. To link thermal responses of MR contrasts with molecular signatures, gene expression profiling will be performed. The aim is to understand the thermal properties of healthy and pathological tissues and explore the use of temperature modulation as a therapeutic tool. ThermalMR will eradicate the main barriers to the study and use of temperature - a critical dimension of life that is of intense clinical interest, but so far very poorly understood. This approach opens an entirely new research field of thermal phenotyping: where physics, biology and medicine meet.
Max ERC Funding
2 043 805 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym TICE
Project TRANSCRIPTOMICS IN CANCER EPIDEMIOLOGY
Researcher (PI) Eiliv Lund
Host Institution (HI) UNIVERSITETET I TROMSOE - NORGES ARKTISKE UNIVERSITET
Call Details Advanced Grant (AdG), LS7, ERC-2008-AdG
Summary NOWAC is the first prospective study with a globolomic design. This is an extension of the current cohort study with its questionnaire information and biological material for analysis of biomarkers, proteomics and single nucleotide polymorphisms (SNPs). The design of NOWAC adds biological material for analysis of the transcriptome in prospectively collected buffered peripheral blood samples, the postgenome biobank. Further, both peripheral blood and tumor tissue are collected from breast cancer patients diagnosed within the cohort together with matched controls. The latter biological material gives a new multidimensional design with a unique biological material at the end-point. The transcriptomic analysis will include both mRNA and miRNA as new technology (microarray and massive parallel sequencing) allows large scale studies. miRNAs could be promising markers for pathways analysis related to the carcinogenic process and for diagnosis and screening tests of breast cancer. These high-troughput technologies have analyses challenges both in bioinformatics and biostatistics therefore success depends on the development of new analytical strategies.This novel design is the observational counterpart to systems biology, or systems epidemiology. Systems epidemiology will seek to understand biological processes by integrating observational derived pathways information into the current prospective design. A true interdisciplinary approach has been implemented. The upside is the potential for an improved understanding of causality in epidemiology by opening up for quantification of traditional criteria of biological plausibility in a more complete biological model. The postgenome biobank with 50 000 participants out of the 172 000 participants in NOWAC and its unique national design and richness of biological material makes it a very strong case for interdisciplinary collaboration based on a population-based study representative of the real and complex lifestyle environment.
Summary
NOWAC is the first prospective study with a globolomic design. This is an extension of the current cohort study with its questionnaire information and biological material for analysis of biomarkers, proteomics and single nucleotide polymorphisms (SNPs). The design of NOWAC adds biological material for analysis of the transcriptome in prospectively collected buffered peripheral blood samples, the postgenome biobank. Further, both peripheral blood and tumor tissue are collected from breast cancer patients diagnosed within the cohort together with matched controls. The latter biological material gives a new multidimensional design with a unique biological material at the end-point. The transcriptomic analysis will include both mRNA and miRNA as new technology (microarray and massive parallel sequencing) allows large scale studies. miRNAs could be promising markers for pathways analysis related to the carcinogenic process and for diagnosis and screening tests of breast cancer. These high-troughput technologies have analyses challenges both in bioinformatics and biostatistics therefore success depends on the development of new analytical strategies.This novel design is the observational counterpart to systems biology, or systems epidemiology. Systems epidemiology will seek to understand biological processes by integrating observational derived pathways information into the current prospective design. A true interdisciplinary approach has been implemented. The upside is the potential for an improved understanding of causality in epidemiology by opening up for quantification of traditional criteria of biological plausibility in a more complete biological model. The postgenome biobank with 50 000 participants out of the 172 000 participants in NOWAC and its unique national design and richness of biological material makes it a very strong case for interdisciplinary collaboration based on a population-based study representative of the real and complex lifestyle environment.
Max ERC Funding
2 300 000 €
Duration
Start date: 2009-01-01, End date: 2014-06-30
Project acronym TIE2+MONOCYTES
Project Tie2-expressing monocytes: Role in tumor angiogenesis and therapeutic targeting
Researcher (PI) Michele De Palma
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Starting Grant (StG), LS7, ERC-2009-StG
Summary Recent data indicated that tumor-infiltrating myeloid cells promote tumor angiogenesis. We contributed to this concept by showing that Tie2-expressing monocytes (TEMs) have a requisite role in this process. Indeed, the specific elimination of TEMs inhibits tumor angiogenesis and growth in several models. Yet, little is known of the biological bases of TEMs activity in tumors. Building upon my previous studies, I will provide a thorough characterization of the precise identity of TEMs and of their biological role in mouse tumor models. I will perform comparative gene expression studies and analyze the developmental relationship between TEMs and other monocyte-lineage cells. By exploiting state-of-the-art genetic strategies, including novel gene knockdown platforms and exogenously- and microRNA-regulated vectors, I will identify and validate molecular pathways that may be targeted to selectively inhibit TEMs activity in tumors. I recently showed that TEMs can be turned into efficient and therapeutically effective vehicles for the targeted delivery of interferon-alpha to tumors. I will now implement preclinical models, including human hematochimeric mice, that will better assess the safety and feasibility of this new delivery strategy. Finally, I will assess the relevance of TEMs in metastasis, and exploit them to constrain metastatic dissemination and growth, either by a cell depletion approach or by delivering interferon specifically at the metastatic niche. The results of these studies will increase significantly our knowledge of the biological functions of proangiogenic monocytes in tumor development, and may improve cancer therapies by enlightening novel and yet unrecognized therapeutic targets and by providing proof-of-feasibility of a new gene therapy strategy.
Summary
Recent data indicated that tumor-infiltrating myeloid cells promote tumor angiogenesis. We contributed to this concept by showing that Tie2-expressing monocytes (TEMs) have a requisite role in this process. Indeed, the specific elimination of TEMs inhibits tumor angiogenesis and growth in several models. Yet, little is known of the biological bases of TEMs activity in tumors. Building upon my previous studies, I will provide a thorough characterization of the precise identity of TEMs and of their biological role in mouse tumor models. I will perform comparative gene expression studies and analyze the developmental relationship between TEMs and other monocyte-lineage cells. By exploiting state-of-the-art genetic strategies, including novel gene knockdown platforms and exogenously- and microRNA-regulated vectors, I will identify and validate molecular pathways that may be targeted to selectively inhibit TEMs activity in tumors. I recently showed that TEMs can be turned into efficient and therapeutically effective vehicles for the targeted delivery of interferon-alpha to tumors. I will now implement preclinical models, including human hematochimeric mice, that will better assess the safety and feasibility of this new delivery strategy. Finally, I will assess the relevance of TEMs in metastasis, and exploit them to constrain metastatic dissemination and growth, either by a cell depletion approach or by delivering interferon specifically at the metastatic niche. The results of these studies will increase significantly our knowledge of the biological functions of proangiogenic monocytes in tumor development, and may improve cancer therapies by enlightening novel and yet unrecognized therapeutic targets and by providing proof-of-feasibility of a new gene therapy strategy.
Max ERC Funding
1 311 900 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym TIL-FIT
Project Increasing the fitness of tumor-infiltrating T cells for cellular immunotherapy
Researcher (PI) Roger GEIGER
Host Institution (HI) FONDAZIONE PER L ISTITUTO DI RICERCA IN BIOMEDICINA
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Adoptive T cell therapies (ACTs) are emerging as a promising strategy to treat cancer. Tumor-infiltrating lymphocytes (TILs) are expanded ex vivo, selected for recognition of neoantigens, further expanded and then infused back into patients. This procedure requires extensive culturing and expansion of TILs during which many T cell clonotypes are lost. As tumor-reactive TILs are often exhausted and tend to be overgrown by functional, non-specific T cells in culture, the chance to identify potent tumor-reactive T cells dramatically decreases. Moreover, extensive expansion of T cells diminishes their anti-tumor activity and persistence in the body after adoptive transfers. Thus, improving the fitness of T cells is crucial to increase the success rate of ACTs and make this therapy accessible to a broad spectrum of cancer patients. Our first aim is to increase the fitness of T cells by designing metabolic and pharmacological interventions based on proteomic profiles of TILs from patients with liver cancer. Second, we will use machine-learning algorithms for the extraction of signatures to predict whether TILs grow well in culture, require and respond to metabolic interventions, or cannot be revitalized and do not grow at all. To deal with non-growing T cells, we aim at establishing a microfluidics-based workflow to graft the entire T cell receptor (TCR) repertoire from thousands of non-growing TILs onto fast growing Jurkat cells. After selecting Jurkat cells that recognize neoantigens, their TCRs will be expressed on naïve T cells obtained from the patient’s blood that are fit and suitable for ACT. This project will contribute to a better understanding of the T cell response to liver cancer and help increasing the success of personalized ACTs for solid tumors.
Summary
Adoptive T cell therapies (ACTs) are emerging as a promising strategy to treat cancer. Tumor-infiltrating lymphocytes (TILs) are expanded ex vivo, selected for recognition of neoantigens, further expanded and then infused back into patients. This procedure requires extensive culturing and expansion of TILs during which many T cell clonotypes are lost. As tumor-reactive TILs are often exhausted and tend to be overgrown by functional, non-specific T cells in culture, the chance to identify potent tumor-reactive T cells dramatically decreases. Moreover, extensive expansion of T cells diminishes their anti-tumor activity and persistence in the body after adoptive transfers. Thus, improving the fitness of T cells is crucial to increase the success rate of ACTs and make this therapy accessible to a broad spectrum of cancer patients. Our first aim is to increase the fitness of T cells by designing metabolic and pharmacological interventions based on proteomic profiles of TILs from patients with liver cancer. Second, we will use machine-learning algorithms for the extraction of signatures to predict whether TILs grow well in culture, require and respond to metabolic interventions, or cannot be revitalized and do not grow at all. To deal with non-growing T cells, we aim at establishing a microfluidics-based workflow to graft the entire T cell receptor (TCR) repertoire from thousands of non-growing TILs onto fast growing Jurkat cells. After selecting Jurkat cells that recognize neoantigens, their TCRs will be expressed on naïve T cells obtained from the patient’s blood that are fit and suitable for ACT. This project will contribute to a better understanding of the T cell response to liver cancer and help increasing the success of personalized ACTs for solid tumors.
Max ERC Funding
1 406 250 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym TOPAS
Project Towards the Quantal Nature of Receptor/cAMP Signals
Researcher (PI) Martin Lohse
Host Institution (HI) JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG
Call Details Advanced Grant (AdG), LS7, ERC-2008-AdG
Summary "Most drugs act via cell surface receptors. Some receptors signal to ion channels, while others regulate 2nd messengers, most importantly cAMP. Ion channels can be resolved at the single channel level using patch clamp analysis; they switch between discrete ""on"" and ""off"" states. In contrast, current techniques to analyze cAMP-signals are quite global and generally require destruction of the sample. Therefore, the activation mechanisms and switching behaviour of receptors signalling to cAMP are largely unknown. This project postulates minimal quantal cAMP-signals that are triggered by individual receptors. We aim to discover these quantal cAMP-signals, to characterize their temporal and spatial patterns, and to determine factors that influence them. To do so, we will develop a microscopic technology to image cAMP-signals with high sensitivity and resolution. We have already developed a first generation of cAMP-sensors that can be expressed in cells and respond to cAMP with a change in fluorescence resonance energy transfer (FRET). We will carry this technology to the sensitivity required for the postulated quantal cAMP-signals and - develop new FRET-sensors for cAMP with much greater brightness, amplitude and sensitivity, - build a specially designed total internal reflection fluorescence (TIRF) microscope to image the sub-membrane region of intact cells, - apply the technology to systems of increasing biological complexity: (a) isolated thyroid cells, where cAMP-signals can be compartmentalized, (b) intact thyroid follicles, where cAMP-signals can be triggered from various cellular sites, and (c) individual neurons in Drosophila brain, which are involved in a defined learning process. We believe that the ability to analyze 2nd messenger responses from individual receptors will open the way to a molecular understanding of receptor function and cAMP-signalling and provide a widely applicable technology and a mechanistic basis for receptor-directed drug development."
Summary
"Most drugs act via cell surface receptors. Some receptors signal to ion channels, while others regulate 2nd messengers, most importantly cAMP. Ion channels can be resolved at the single channel level using patch clamp analysis; they switch between discrete ""on"" and ""off"" states. In contrast, current techniques to analyze cAMP-signals are quite global and generally require destruction of the sample. Therefore, the activation mechanisms and switching behaviour of receptors signalling to cAMP are largely unknown. This project postulates minimal quantal cAMP-signals that are triggered by individual receptors. We aim to discover these quantal cAMP-signals, to characterize their temporal and spatial patterns, and to determine factors that influence them. To do so, we will develop a microscopic technology to image cAMP-signals with high sensitivity and resolution. We have already developed a first generation of cAMP-sensors that can be expressed in cells and respond to cAMP with a change in fluorescence resonance energy transfer (FRET). We will carry this technology to the sensitivity required for the postulated quantal cAMP-signals and - develop new FRET-sensors for cAMP with much greater brightness, amplitude and sensitivity, - build a specially designed total internal reflection fluorescence (TIRF) microscope to image the sub-membrane region of intact cells, - apply the technology to systems of increasing biological complexity: (a) isolated thyroid cells, where cAMP-signals can be compartmentalized, (b) intact thyroid follicles, where cAMP-signals can be triggered from various cellular sites, and (c) individual neurons in Drosophila brain, which are involved in a defined learning process. We believe that the ability to analyze 2nd messenger responses from individual receptors will open the way to a molecular understanding of receptor function and cAMP-signalling and provide a widely applicable technology and a mechanistic basis for receptor-directed drug development."
Max ERC Funding
2 493 358 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym TRANSPOSOSTRESS
Project Impact of stress-induced transposon activities on human disease
Researcher (PI) Zsuzsanna Izsvák
Host Institution (HI) MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Call Details Advanced Grant (AdG), LS7, ERC-2011-ADG_20110310
Summary The evolutionary success of transposable elements (TEs) is underscored by the finding that about 45% of the human genome is TE-derived. However, recent high throughput approach studies indicate that the impact of TE-associated activities was seriously underestimated. The first objective is to investigate the impact of TE-derived activities on the human genome in general and on disease mechanisms in particular, based on the central premise that some of these activities are stress-induced. To model how a vertebrate-specific transposon responds to stress signals in human cells, I will study molecular interactions of the Sleeping Beauty (SB) transposon with host cellular mechanisms to understand how stress-signalling and response triggers transposon activation. My second aim is to decipher the relationship between stress-induced activation of endogenous TEs and TE-derived regulatory sequences and human disease. I aim at investigating conditions and the consequences of activation of a particular copy of the MERmaid transposon located in the Sin3B transcriptional corepressor, frequently observed in cancer. The impact of global epigenetic remodelling will be investigated in the model of a complete (induced pluripotency) and partial (trans-differentiation) epigenetic reprogramming. In parallel, I aim at translating experience accumulated in TE research to cutting-edge technologies. First, the SB transposon will be adopted as a safe, therapeutic vector to treat age-dependent blindness (AMD). Second, a mutagenic SB vector will be used in a forward genetic screen to decipher a genetic network that protects against hormone-induced mammary cancer. The anticipated output of my research programme is a refined understanding of the consequences of environmental stress on our genome mediated by TE-derived sequences. The project is expected to provide an effective bridge between basic research and clinical- as well as technological translation of a novel gene transfer technology.
Summary
The evolutionary success of transposable elements (TEs) is underscored by the finding that about 45% of the human genome is TE-derived. However, recent high throughput approach studies indicate that the impact of TE-associated activities was seriously underestimated. The first objective is to investigate the impact of TE-derived activities on the human genome in general and on disease mechanisms in particular, based on the central premise that some of these activities are stress-induced. To model how a vertebrate-specific transposon responds to stress signals in human cells, I will study molecular interactions of the Sleeping Beauty (SB) transposon with host cellular mechanisms to understand how stress-signalling and response triggers transposon activation. My second aim is to decipher the relationship between stress-induced activation of endogenous TEs and TE-derived regulatory sequences and human disease. I aim at investigating conditions and the consequences of activation of a particular copy of the MERmaid transposon located in the Sin3B transcriptional corepressor, frequently observed in cancer. The impact of global epigenetic remodelling will be investigated in the model of a complete (induced pluripotency) and partial (trans-differentiation) epigenetic reprogramming. In parallel, I aim at translating experience accumulated in TE research to cutting-edge technologies. First, the SB transposon will be adopted as a safe, therapeutic vector to treat age-dependent blindness (AMD). Second, a mutagenic SB vector will be used in a forward genetic screen to decipher a genetic network that protects against hormone-induced mammary cancer. The anticipated output of my research programme is a refined understanding of the consequences of environmental stress on our genome mediated by TE-derived sequences. The project is expected to provide an effective bridge between basic research and clinical- as well as technological translation of a novel gene transfer technology.
Max ERC Funding
1 940 725 €
Duration
Start date: 2013-01-01, End date: 2018-12-31
Project acronym XHaLe
Project Hanover experimental lung research project
Researcher (PI) Danny David Jonigk
Host Institution (HI) MEDIZINISCHE HOCHSCHULE HANNOVER
Call Details Consolidator Grant (CoG), LS7, ERC-2017-COG
Summary Non-neoplastic lung diseases (NNLD), such as COPD and interstitial lung diseases rank second among the causes of death and NNLD appear as a growing EU wide challenge. They are characterized by irreversible remodeling with a relentless loss of lung function and a 5-year survival of only 30%. This dysfunctional reaction to injury can be triggered by particulate matters with macrophages (MO) as the key regulators. Wholesale therapeutic suppression of the inflammome actually increases the risk of death, whereas targeted therapy of signalling cascades by novel pharmaceuticals, e.g. nintedanib, only slows disease progression. Thus lung transplantation remains the ultima ratio. However, available grafts are limited, treatment costs are high and the 5-year survival barely surpasses 50%. Therefore novel approaches to understand, prevent and ultimately cure NNLDs are urgently needed. Towards this goal my group focusses on both, the main effector cell in NNLD, the myofibroblast, and the inflammome and particularly MOs, as these orchestrate both, lung healing and remodeling. Modulating the pulmonary immune system, rather than subduing it, holds significant promise. To this end, we have to understand the very early events in NNLDs. There are 2 major obstacles for efficient research: i) the lack of adequate animal models and ii) the availability of human specimens. Therefore we established a unique platform for NNLD: we utilize fresh explanted human lungs from Europe’s largest LuTx program and set up a singular 24h/7d workflow, ensuring short ischemia and tissue viability. In the last years, we have worked up over 500 lungs, acted as an international multiplier for pulmonary research, patented new imaging techniques and described novel diseases. Our understanding MO biology in NNLDs showed us the great potential in macrophages. Now we are going to use these macrophages as potential therapeutics. Hereby we will make a difference in translational medicine in Europe and the world.
Summary
Non-neoplastic lung diseases (NNLD), such as COPD and interstitial lung diseases rank second among the causes of death and NNLD appear as a growing EU wide challenge. They are characterized by irreversible remodeling with a relentless loss of lung function and a 5-year survival of only 30%. This dysfunctional reaction to injury can be triggered by particulate matters with macrophages (MO) as the key regulators. Wholesale therapeutic suppression of the inflammome actually increases the risk of death, whereas targeted therapy of signalling cascades by novel pharmaceuticals, e.g. nintedanib, only slows disease progression. Thus lung transplantation remains the ultima ratio. However, available grafts are limited, treatment costs are high and the 5-year survival barely surpasses 50%. Therefore novel approaches to understand, prevent and ultimately cure NNLDs are urgently needed. Towards this goal my group focusses on both, the main effector cell in NNLD, the myofibroblast, and the inflammome and particularly MOs, as these orchestrate both, lung healing and remodeling. Modulating the pulmonary immune system, rather than subduing it, holds significant promise. To this end, we have to understand the very early events in NNLDs. There are 2 major obstacles for efficient research: i) the lack of adequate animal models and ii) the availability of human specimens. Therefore we established a unique platform for NNLD: we utilize fresh explanted human lungs from Europe’s largest LuTx program and set up a singular 24h/7d workflow, ensuring short ischemia and tissue viability. In the last years, we have worked up over 500 lungs, acted as an international multiplier for pulmonary research, patented new imaging techniques and described novel diseases. Our understanding MO biology in NNLDs showed us the great potential in macrophages. Now we are going to use these macrophages as potential therapeutics. Hereby we will make a difference in translational medicine in Europe and the world.
Max ERC Funding
1 989 250 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym ZAUBERKUGEL
Project Fulfilling Paul Ehrlich’s Dream: therapeutics with activity on demand
Researcher (PI) Dario Antonio Ansano Neri
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Advanced Grant (AdG), LS7, ERC-2014-ADG
Summary "Paul Ehrlich was the first scientist to postulate that if a compound could be made that selectively targeted disease-causing cells, then this agent could be used for the delivery of a toxin, which would enable a pharmacotherapy of unprecedented potency and selectivity. With this procedure, a ""magic bullet"" (Zauberkugel, his term for an ideal therapeutic agent) would be created, that killed diseased cells while sparing normal tissues.
The concept of a ""magic bullet"" was to some extent realized by the invention of monoclonal antibodies, as these molecules provide a very specific binding affinity to their cognate target. However, monoclonal antibodies used as single agents are typically not able to induce cures for cancer or chronic inflammatory diseases. More recently, intense academic and industrial research activities have aimed at “arming” monoclonal antibodies with drugs or cytokines, in order to preferentially deliver these therapeutic payloads to the site of disease. Unfortunately, in most cases, ""armed"" antibody products still cause unacceptable toxicities, which prevent escalation to potentially curative dose regimens.
In this Project, I outline a therapeutic strategy, which relies on the use of extremely specific tumor targeting agents, for the selective delivery of payloads, which can be conditionally activated at the site of disease. Methodologies for the conditional generation of active payloads include the stepwise non-covalent assembly of cytokines and the controlled release of cytotoxic drugs at suitable time points after injection, when the concentration of therapeutic agent in normal organs is acceptably low. Response to therapy will be profiled using innovative proteomic methodologies, based on HLA-peptidome analysis.
Pharmaceutical agents with “activity on demand” hold a considerable potential not only for the therapy of cancer, but also for the treatment of other serious diseases, including certain highly debilitating chronic inflammatory condition"
Summary
"Paul Ehrlich was the first scientist to postulate that if a compound could be made that selectively targeted disease-causing cells, then this agent could be used for the delivery of a toxin, which would enable a pharmacotherapy of unprecedented potency and selectivity. With this procedure, a ""magic bullet"" (Zauberkugel, his term for an ideal therapeutic agent) would be created, that killed diseased cells while sparing normal tissues.
The concept of a ""magic bullet"" was to some extent realized by the invention of monoclonal antibodies, as these molecules provide a very specific binding affinity to their cognate target. However, monoclonal antibodies used as single agents are typically not able to induce cures for cancer or chronic inflammatory diseases. More recently, intense academic and industrial research activities have aimed at “arming” monoclonal antibodies with drugs or cytokines, in order to preferentially deliver these therapeutic payloads to the site of disease. Unfortunately, in most cases, ""armed"" antibody products still cause unacceptable toxicities, which prevent escalation to potentially curative dose regimens.
In this Project, I outline a therapeutic strategy, which relies on the use of extremely specific tumor targeting agents, for the selective delivery of payloads, which can be conditionally activated at the site of disease. Methodologies for the conditional generation of active payloads include the stepwise non-covalent assembly of cytokines and the controlled release of cytotoxic drugs at suitable time points after injection, when the concentration of therapeutic agent in normal organs is acceptably low. Response to therapy will be profiled using innovative proteomic methodologies, based on HLA-peptidome analysis.
Pharmaceutical agents with “activity on demand” hold a considerable potential not only for the therapy of cancer, but also for the treatment of other serious diseases, including certain highly debilitating chronic inflammatory condition"
Max ERC Funding
2 000 000 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
