Project acronym CELLNAIVETY
Project Deciphering the Molecular Foundations and Functional Competence of Alternative Human Naïve Pluripotent Stem Cells
Researcher (PI) Yaqub HANNA
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary An important goal of stem cell therapy is to create “customized” cells that are genetically identical to the patient, which upon transplantation can restore damaged tissues. Such cells can be obtained by in vitro direct reprogramming of somatic cells into embryonic stem (ES)-like cells, termed induced pluripotent stem cells (iPSC). This approach also opens possibilities for modelling human diseases in vitro. However, major hurdles remain that restrain fulfilling conventional human iPSC/ESC potential, as they reside in an advanced primed pluripotent state. Such hurdles include limited differentiation capacity and functional variability. Further, in vitro iPSC based research platforms are simplistic and iPSC based “humanized” chimeric mouse models may be of great benefit.
The recent isolation of distinct and new “mouse-like” naive pluripotent states in humans that correspond to earlier embryonic developmental state(s), constitutes a paradigm shift and may alleviate limitations of conventional primed iPSCs/ESCs. Thus, our proposal aims at dissecting the human naïve pluripotent state(s) and to unveil pathways that facilitate their unique identity and flexible programming.
Specific goals: 1) Transcriptional and Epigenetic Design Principles of Human Naïve Pluripotency 2) Signalling Principles Governing Human Naïve Pluripotency Maintenance and Differentiation 3) Defining Functional Competence and Safety of Human Naïve Pluripotent Stem Cells in vitro 4) Novel human naïve iPSC based cross-species chimeric mice for studying human differentiation and disease modelling in vivo. These aims will be conducted by utilizing engineered human iPSC/ESC models, CRISPR/Cas9 genome-wide screening, advanced microscopy and ex-vivo whole embryo culture methods. Our goals will synergistically lead to the design of strategies that will accelerate the safe medical application of human naive pluripotent stem cells and their use in disease specific modelling and applied stem cell research.
Summary
An important goal of stem cell therapy is to create “customized” cells that are genetically identical to the patient, which upon transplantation can restore damaged tissues. Such cells can be obtained by in vitro direct reprogramming of somatic cells into embryonic stem (ES)-like cells, termed induced pluripotent stem cells (iPSC). This approach also opens possibilities for modelling human diseases in vitro. However, major hurdles remain that restrain fulfilling conventional human iPSC/ESC potential, as they reside in an advanced primed pluripotent state. Such hurdles include limited differentiation capacity and functional variability. Further, in vitro iPSC based research platforms are simplistic and iPSC based “humanized” chimeric mouse models may be of great benefit.
The recent isolation of distinct and new “mouse-like” naive pluripotent states in humans that correspond to earlier embryonic developmental state(s), constitutes a paradigm shift and may alleviate limitations of conventional primed iPSCs/ESCs. Thus, our proposal aims at dissecting the human naïve pluripotent state(s) and to unveil pathways that facilitate their unique identity and flexible programming.
Specific goals: 1) Transcriptional and Epigenetic Design Principles of Human Naïve Pluripotency 2) Signalling Principles Governing Human Naïve Pluripotency Maintenance and Differentiation 3) Defining Functional Competence and Safety of Human Naïve Pluripotent Stem Cells in vitro 4) Novel human naïve iPSC based cross-species chimeric mice for studying human differentiation and disease modelling in vivo. These aims will be conducted by utilizing engineered human iPSC/ESC models, CRISPR/Cas9 genome-wide screening, advanced microscopy and ex-vivo whole embryo culture methods. Our goals will synergistically lead to the design of strategies that will accelerate the safe medical application of human naive pluripotent stem cells and their use in disease specific modelling and applied stem cell research.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-11-01, End date: 2022-10-31
Project acronym DIAG-CANCER
Project Diagnosis, Screening and Monitoring of Cancer Diseases via Exhaled Breath Using an Array of Nanosensors
Researcher (PI) Hossam Haick
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Cancer is rapidly becoming the greatest health hazard of our days. The most widespread cancers, are lung cancer (LC), breast cancer (BC), colorectal cancer (CC), and prostate cancer (PC). The impact of the various techniques used for diagnosis, screening and monitoring
these cancers is either uncertain and/or inconvenient for the patients. This proposal aims to create a low-cost, easy-to-use and noninvasive screening method for LC, BC, CC, and PC based on breath testing with a novel nanosensors approach. With this in mind, we propose to:
(a) modify an array of nanosensors based on Au nanoparticles for obtaining highly-sensitive detection levels of breath biomarkers of cancer; and
(b) investigate the use of the developed array in a clinical study.
Towards this end, we will collect suitable breath samples from patients and healthy controls in a clinical trial and test the feasibility of the device to detect LC, BC, CC, and PC, also in the presence of other diseases.
We will then investigate possible ways to identify the stage of the disease, monitor the response to cancer
treatment, and to identify cancer subtypes. Further, we propose that the device can be used for monitoring of cancer patients during and after treatment. The chemical nature of the cancer biomarkers will be identified through spectrometry techniques.
The proposed approach would be used outside specialist settings and could considerably lessen the burden on the health budgets, both through the low cost of the proposed all-inclusive cancer test, and through earlier and, hence, more cost-effective cancer treatment.
Summary
Cancer is rapidly becoming the greatest health hazard of our days. The most widespread cancers, are lung cancer (LC), breast cancer (BC), colorectal cancer (CC), and prostate cancer (PC). The impact of the various techniques used for diagnosis, screening and monitoring
these cancers is either uncertain and/or inconvenient for the patients. This proposal aims to create a low-cost, easy-to-use and noninvasive screening method for LC, BC, CC, and PC based on breath testing with a novel nanosensors approach. With this in mind, we propose to:
(a) modify an array of nanosensors based on Au nanoparticles for obtaining highly-sensitive detection levels of breath biomarkers of cancer; and
(b) investigate the use of the developed array in a clinical study.
Towards this end, we will collect suitable breath samples from patients and healthy controls in a clinical trial and test the feasibility of the device to detect LC, BC, CC, and PC, also in the presence of other diseases.
We will then investigate possible ways to identify the stage of the disease, monitor the response to cancer
treatment, and to identify cancer subtypes. Further, we propose that the device can be used for monitoring of cancer patients during and after treatment. The chemical nature of the cancer biomarkers will be identified through spectrometry techniques.
The proposed approach would be used outside specialist settings and could considerably lessen the burden on the health budgets, both through the low cost of the proposed all-inclusive cancer test, and through earlier and, hence, more cost-effective cancer treatment.
Max ERC Funding
1 200 000 €
Duration
Start date: 2011-01-01, End date: 2014-12-31
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 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 MGUS screening RCT
Project Screening for monoclonal gammopathy of undetermined significance: A population-based randomized clinical trial
Researcher (PI) Sigurdur Yngvi KRISTINSSON
Host Institution (HI) HASKOLI ISLANDS
Call Details Starting Grant (StG), LS7, ERC-2016-STG
Summary Monoclonal gammopathy of undetermined significance (MGUS) is a very common precursor condition to multiple myeloma (MM), and related diseases, and can be found in approximately 4-5% of individuals over the age of 50 years. MM is always preceded by MGUS. Current risk stratification schemes, designed to predict those that will progress, are based on retrospective data and rely almost solely on serum protein markers. While they can differentiate high and low-risk patients, they cannot predict outcome for individual patients, are not integrated with one another, and have limited biological correlation. Based on retrospective data, it is recommended that individuals with MGUS are followed indefinitely; however no prospective study has ever been performed to evaluate this or identify optimal monitoring in MGUS individuals. We recently showed that MM patients with a prior knowledge of MGUS had superior survival compared to MM patients without, which raises the question whether routine screening for MGUS in the population might improve survival. To evaluate the impact of screening for MGUS on overall survival, to provide evidence for the optimal MGUS follow-up, and to integrate biological, imaging, and germline genetic markers in evaluating individual risk of progression, we propose to invite all individuals >50 years in Iceland (N=104,000) to participate in a screening study for MGUS. This will be done by utilizing already present infrastructure for screening in Iceland and the fact that most individuals >50 years have their blood drawn for various reasons during 3 years. We plan to perform electrophoresis and free light chain analyses in these individuals to diagnose MGUS. Individuals with MGUS will be invited to be included in a randomized clinical trial with 3 different arms to identify the optimal work-up and follow-up strategy and to build a new risk model for progression. Our large, unique, population-based study has major clinical and scientific implications.
Summary
Monoclonal gammopathy of undetermined significance (MGUS) is a very common precursor condition to multiple myeloma (MM), and related diseases, and can be found in approximately 4-5% of individuals over the age of 50 years. MM is always preceded by MGUS. Current risk stratification schemes, designed to predict those that will progress, are based on retrospective data and rely almost solely on serum protein markers. While they can differentiate high and low-risk patients, they cannot predict outcome for individual patients, are not integrated with one another, and have limited biological correlation. Based on retrospective data, it is recommended that individuals with MGUS are followed indefinitely; however no prospective study has ever been performed to evaluate this or identify optimal monitoring in MGUS individuals. We recently showed that MM patients with a prior knowledge of MGUS had superior survival compared to MM patients without, which raises the question whether routine screening for MGUS in the population might improve survival. To evaluate the impact of screening for MGUS on overall survival, to provide evidence for the optimal MGUS follow-up, and to integrate biological, imaging, and germline genetic markers in evaluating individual risk of progression, we propose to invite all individuals >50 years in Iceland (N=104,000) to participate in a screening study for MGUS. This will be done by utilizing already present infrastructure for screening in Iceland and the fact that most individuals >50 years have their blood drawn for various reasons during 3 years. We plan to perform electrophoresis and free light chain analyses in these individuals to diagnose MGUS. Individuals with MGUS will be invited to be included in a randomized clinical trial with 3 different arms to identify the optimal work-up and follow-up strategy and to build a new risk model for progression. Our large, unique, population-based study has major clinical and scientific implications.
Max ERC Funding
1 474 304 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
Project acronym onCOMBINE
Project Towards evidence-based combinations of approved and novel cancer drugs
Researcher (PI) Yosef YARDEN
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Background: Molecular targeted therapy (TT; e.g., monoclonal antibodies, mAbs, and protein kinase inhibitors, PKIs) intercepts oncogene and other addictions of tumours. However, unlike chemotherapy, which employs cocktails of drugs, only rarely does TT harness poly-pharmacology. Because lung cancer is the major cause of oncology related fatalities and many driver mutations are known, this disease offers opportunities for establishing and generalizing novel TT combinations and their interface with the immune system.
Working hypothesis: High granularity maps of compensatory loops evoked by TT, along with deeper understanding of mechanisms underlying drug action, resistance and interactions with lymphoid/myeloid cells, will conceptualize drug combinations able to persistently inhibit tumours, while inducing only limited toxicities.
Goal and specific aims: Addressing resistance to TT, potential synergies and the immune system, we will employ lung cancer models driven by mutant EGFR, HER2, MET or AXL. Phosphoproteomics, transcriptomics and RNA interference, will enable mapping adaptations evoked by specific drugs. Once identified, we will test combinations of interceptors able to inhibit the primary target as well as the emerging, resistance-conferring route(s). Next, we will determine the mechanisms of action of selected interceptors (e.g., apoptosis, immunological cytotoxicity and senescence) as bases for optimising effective combinations. Homo-combinations of antibodies (i.e., antibodies recognising distinct epitopes of a receptor), hetero-combinations targeting distinct signalling and immune receptors, and combinations with PKIs will be examined in animal models.
Significance: More than 30 PKIs and >25 mAbs are approved in oncology, but most are used as monotherapies. Detailed knowledge of adaptation-driven resistance, mechanisms of drug action and immune effectors, will guide the long awaited application of TT combinations in oncology, including lung cancer.
Summary
Background: Molecular targeted therapy (TT; e.g., monoclonal antibodies, mAbs, and protein kinase inhibitors, PKIs) intercepts oncogene and other addictions of tumours. However, unlike chemotherapy, which employs cocktails of drugs, only rarely does TT harness poly-pharmacology. Because lung cancer is the major cause of oncology related fatalities and many driver mutations are known, this disease offers opportunities for establishing and generalizing novel TT combinations and their interface with the immune system.
Working hypothesis: High granularity maps of compensatory loops evoked by TT, along with deeper understanding of mechanisms underlying drug action, resistance and interactions with lymphoid/myeloid cells, will conceptualize drug combinations able to persistently inhibit tumours, while inducing only limited toxicities.
Goal and specific aims: Addressing resistance to TT, potential synergies and the immune system, we will employ lung cancer models driven by mutant EGFR, HER2, MET or AXL. Phosphoproteomics, transcriptomics and RNA interference, will enable mapping adaptations evoked by specific drugs. Once identified, we will test combinations of interceptors able to inhibit the primary target as well as the emerging, resistance-conferring route(s). Next, we will determine the mechanisms of action of selected interceptors (e.g., apoptosis, immunological cytotoxicity and senescence) as bases for optimising effective combinations. Homo-combinations of antibodies (i.e., antibodies recognising distinct epitopes of a receptor), hetero-combinations targeting distinct signalling and immune receptors, and combinations with PKIs will be examined in animal models.
Significance: More than 30 PKIs and >25 mAbs are approved in oncology, but most are used as monotherapies. Detailed knowledge of adaptation-driven resistance, mechanisms of drug action and immune effectors, will guide the long awaited application of TT combinations in oncology, including lung cancer.
Max ERC Funding
2 488 306 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
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 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 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 StressGene
Project The Genetics of Morbidity and Survival in Response to Significant Life Stressors
Researcher (PI) Unnur VALDIMARSDÓTTIR
Host Institution (HI) HASKOLI ISLANDS
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary Significant life stressors – including death of loved ones, being diagnosed with a life-threatening illness, and exposure to natural disasters or violence – are well-documented risk factors of ill health, disability and premature mortality. Why some individuals remain healthy while others remiss to adverse symptoms, disease or death after exposure to such life stressors remains unclear. The overarching aim of this research program is to advance current understanding of the potential genetic contribution to varying trajectories of health following exposure to significant life stressors.
The program leverages the registries of major diseases and mortality covering the whole Icelandic nation (N=330.000) and the unique genetic- and genealogical resources at deCODE Genetics to perform genome-wide association studies (GWAS) on the varying risks of overall mortality and major diseases (including psychiatric disorders and cardiovascular disease) after loss of a family member or after receiving a cancer diagnosis. We will further seek to identify sequence variants associated with variation in symptoms of posttraumatic stress disorder (PTSD) in two highly traumatized cohorts: the SAGA cohort of 30.000 Icelandic women with high lifetime prevalence of violence exposure, as well as a cohort of 5.000 Swedes exposed to the 2004 SA-Asian Tsunami. This research program represents the first major attempt to address the potential genetic basis of varying somatic health outcomes after exposure to significant life stressors and, to our knowledge, one of the first comprehensive GWAS on PTSD in European populations.
Virtually everyone is at some point in their life exposed to significant life stressors or trauma; the knowledge gained from this comprehensive research program may facilitate early identification and refined, personalized interventions for the most vulnerable individuals of the large populations worldwide that inevitably will continue to be exposed to trauma.
Summary
Significant life stressors – including death of loved ones, being diagnosed with a life-threatening illness, and exposure to natural disasters or violence – are well-documented risk factors of ill health, disability and premature mortality. Why some individuals remain healthy while others remiss to adverse symptoms, disease or death after exposure to such life stressors remains unclear. The overarching aim of this research program is to advance current understanding of the potential genetic contribution to varying trajectories of health following exposure to significant life stressors.
The program leverages the registries of major diseases and mortality covering the whole Icelandic nation (N=330.000) and the unique genetic- and genealogical resources at deCODE Genetics to perform genome-wide association studies (GWAS) on the varying risks of overall mortality and major diseases (including psychiatric disorders and cardiovascular disease) after loss of a family member or after receiving a cancer diagnosis. We will further seek to identify sequence variants associated with variation in symptoms of posttraumatic stress disorder (PTSD) in two highly traumatized cohorts: the SAGA cohort of 30.000 Icelandic women with high lifetime prevalence of violence exposure, as well as a cohort of 5.000 Swedes exposed to the 2004 SA-Asian Tsunami. This research program represents the first major attempt to address the potential genetic basis of varying somatic health outcomes after exposure to significant life stressors and, to our knowledge, one of the first comprehensive GWAS on PTSD in European populations.
Virtually everyone is at some point in their life exposed to significant life stressors or trauma; the knowledge gained from this comprehensive research program may facilitate early identification and refined, personalized interventions for the most vulnerable individuals of the large populations worldwide that inevitably will continue to be exposed to trauma.
Max ERC Funding
1 998 544 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
