Project acronym ALEM
Project ADDITIONAL LOSSES IN ELECTRICAL MACHINES
Researcher (PI) Matti Antero Arkkio
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Country Finland
Call Details Advanced Grant (AdG), PE8, ERC-2013-ADG
Summary "Electrical motors consume about 40 % of the electrical energy produced in the European Union. About 90 % of this energy is converted to mechanical work. However, 0.5-2.5 % of it goes to so called additional load losses whose exact origins are unknown. Our ambitious aim is to reveal the origins of these losses, build up numerical tools for modeling them and optimize electrical motors to minimize the losses.
As the hypothesis of the research, we assume that the additional losses mainly result from the deterioration of the core materials during the manufacturing process of the machine. By calorimetric measurements, we have found that the core losses of electrical machines may be twice as large as comprehensive loss models predict. The electrical steel sheets are punched, welded together and shrink fit to the frame. This causes residual strains in the core sheets deteriorating their magnetic characteristics. The cutting burrs make galvanic contacts between the sheets and form paths for inter-lamination currents. Another potential source of additional losses are the circulating currents between the parallel strands of random-wound armature windings. The stochastic nature of these potential sources of additional losses puts more challenge on the research.
We shall develop a physical loss model that couples the mechanical strains and electromagnetic losses in electrical steel sheets and apply the new model for comprehensive loss analysis of electrical machines. The stochastic variables related to the core losses and circulating-current losses will be discretized together with the temporal and spatial discretization of the electromechanical field variables. The numerical stochastic loss model will be used to search for such machine constructions that are insensitive to the manufacturing defects. We shall validate the new numerical loss models by electromechanical and calorimetric measurements."
Summary
"Electrical motors consume about 40 % of the electrical energy produced in the European Union. About 90 % of this energy is converted to mechanical work. However, 0.5-2.5 % of it goes to so called additional load losses whose exact origins are unknown. Our ambitious aim is to reveal the origins of these losses, build up numerical tools for modeling them and optimize electrical motors to minimize the losses.
As the hypothesis of the research, we assume that the additional losses mainly result from the deterioration of the core materials during the manufacturing process of the machine. By calorimetric measurements, we have found that the core losses of electrical machines may be twice as large as comprehensive loss models predict. The electrical steel sheets are punched, welded together and shrink fit to the frame. This causes residual strains in the core sheets deteriorating their magnetic characteristics. The cutting burrs make galvanic contacts between the sheets and form paths for inter-lamination currents. Another potential source of additional losses are the circulating currents between the parallel strands of random-wound armature windings. The stochastic nature of these potential sources of additional losses puts more challenge on the research.
We shall develop a physical loss model that couples the mechanical strains and electromagnetic losses in electrical steel sheets and apply the new model for comprehensive loss analysis of electrical machines. The stochastic variables related to the core losses and circulating-current losses will be discretized together with the temporal and spatial discretization of the electromechanical field variables. The numerical stochastic loss model will be used to search for such machine constructions that are insensitive to the manufacturing defects. We shall validate the new numerical loss models by electromechanical and calorimetric measurements."
Max ERC Funding
2 489 949 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym AMETIST
Project Advanced III-V Materials and Processes Enabling Ultrahigh-efficiency ( 50%) Photovoltaics
Researcher (PI) Mircea Dorel GUINA
Host Institution (HI) TAMPEREEN KORKEAKOULUSAATIO SR
Country Finland
Call Details Advanced Grant (AdG), PE8, ERC-2015-AdG
Summary Compound semiconductor solar cells are providing the highest photovoltaic conversion efficiency, yet their performance lacks far behind the theoretical potential. This is a position we will challenge by engineering advanced III-V optoelectronics materials and heterostructures for better utilization of the solar spectrum, enabling efficiencies approaching practical limits. The work is strongly motivated by the global need for renewable energy sources. To this end, AMETIST framework is based on three vectors of excellence in: i) material science and epitaxial processes, ii) advanced solar cells exploiting nanophotonics concepts, and iii) new device fabrication technologies.
Novel heterostructures (e.g. GaInNAsSb, GaNAsBi), providing absorption in a broad spectral range from 0.7 eV to 1.4 eV, will be synthesized and monolithically integrated in tandem cells with up to 8-junctions. Nanophotonic methods for light-trapping, spectral and spatial control of solar radiation will be developed to further enhance the absorption. To ensure a high long-term impact, the project will validate the use of state-of-the-art molecular-beam-epitaxy processes for fabrication of economically viable ultra-high efficiency solar cells. The ultimate efficiency target is to reach a level of 55%. This would enable to generate renewable/ecological/sustainable energy at a levelized production cost below ~7 ¢/kWh, comparable or cheaper than fossil fuels. The work will also bring a new breath of developments for more efficient space photovoltaic systems.
AMETIST will leverage the leading position of the applicant in topical technology areas relevant for the project (i.e. epitaxy of III-N/Bi-V alloys and key achievements concerning GaInNAsSb-based tandem solar cells). Thus it renders a unique opportunity to capitalize on the group expertize and position Europe at the forefront in the global competition for demonstrating more efficient and economically viable photovoltaic technologies.
Summary
Compound semiconductor solar cells are providing the highest photovoltaic conversion efficiency, yet their performance lacks far behind the theoretical potential. This is a position we will challenge by engineering advanced III-V optoelectronics materials and heterostructures for better utilization of the solar spectrum, enabling efficiencies approaching practical limits. The work is strongly motivated by the global need for renewable energy sources. To this end, AMETIST framework is based on three vectors of excellence in: i) material science and epitaxial processes, ii) advanced solar cells exploiting nanophotonics concepts, and iii) new device fabrication technologies.
Novel heterostructures (e.g. GaInNAsSb, GaNAsBi), providing absorption in a broad spectral range from 0.7 eV to 1.4 eV, will be synthesized and monolithically integrated in tandem cells with up to 8-junctions. Nanophotonic methods for light-trapping, spectral and spatial control of solar radiation will be developed to further enhance the absorption. To ensure a high long-term impact, the project will validate the use of state-of-the-art molecular-beam-epitaxy processes for fabrication of economically viable ultra-high efficiency solar cells. The ultimate efficiency target is to reach a level of 55%. This would enable to generate renewable/ecological/sustainable energy at a levelized production cost below ~7 ¢/kWh, comparable or cheaper than fossil fuels. The work will also bring a new breath of developments for more efficient space photovoltaic systems.
AMETIST will leverage the leading position of the applicant in topical technology areas relevant for the project (i.e. epitaxy of III-N/Bi-V alloys and key achievements concerning GaInNAsSb-based tandem solar cells). Thus it renders a unique opportunity to capitalize on the group expertize and position Europe at the forefront in the global competition for demonstrating more efficient and economically viable photovoltaic technologies.
Max ERC Funding
2 492 719 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym ATOP
Project Atomically-engineered nonlinear photonics with two-dimensional layered material superlattices
Researcher (PI) zhipei SUN
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Country Finland
Call Details Advanced Grant (AdG), PE8, ERC-2018-ADG
Summary The project aims at introducing a paradigm shift in the development of nonlinear photonics with atomically-engineered two-dimensional (2D) van der Waals superlattices (2DSs). Monolayer 2D materials have large optical nonlinear susceptibilities, a few orders of magnitude larger than typical traditional bulk materials. However, nonlinear frequency conversion efficiency of monolayer 2D materials is typically weak mainly due to their extremely short interaction length (~atomic scale) and relatively large absorption coefficient (e.g.,>5×10^7 m^-1 in the visible range for graphene and MoS2 after thickness normalization). In this context, I will construct atomically-engineered heterojunctions based 2DSs to significantly enhance the nonlinear optical responses of 2D materials by coherently increasing light-matter interaction length and efficiently creating fundamentally new physical properties (e.g., reducing optical loss and increasing nonlinear susceptibilities).
The concrete project objectives are to theoretically calculate, experimentally fabricate and study optical nonlinearities of 2DSs for next-generation nonlinear photonics at the nanoscale. More specifically, I will use 2DSs as new building blocks to develop three of the most disruptive nonlinear photonic devices: (1) on-chip optical parametric generation sources; (2) broadband Terahertz sources; (3) high-purity photon-pair emitters. These devices will lead to a breakthrough technology to enable highly-integrated, high-efficient and wideband lab-on-chip photonic systems with unprecedented performance in system size, power consumption, flexibility and reliability, ideally fitting numerous growing and emerging applications, e.g. metrology, portable sensing/imaging, and quantum-communications. Based on my proven track record and my pioneering work on 2D materials based photonics and optoelectronics, I believe I will accomplish this ambitious frontier research program with a strong interdisciplinary nature.
Summary
The project aims at introducing a paradigm shift in the development of nonlinear photonics with atomically-engineered two-dimensional (2D) van der Waals superlattices (2DSs). Monolayer 2D materials have large optical nonlinear susceptibilities, a few orders of magnitude larger than typical traditional bulk materials. However, nonlinear frequency conversion efficiency of monolayer 2D materials is typically weak mainly due to their extremely short interaction length (~atomic scale) and relatively large absorption coefficient (e.g.,>5×10^7 m^-1 in the visible range for graphene and MoS2 after thickness normalization). In this context, I will construct atomically-engineered heterojunctions based 2DSs to significantly enhance the nonlinear optical responses of 2D materials by coherently increasing light-matter interaction length and efficiently creating fundamentally new physical properties (e.g., reducing optical loss and increasing nonlinear susceptibilities).
The concrete project objectives are to theoretically calculate, experimentally fabricate and study optical nonlinearities of 2DSs for next-generation nonlinear photonics at the nanoscale. More specifically, I will use 2DSs as new building blocks to develop three of the most disruptive nonlinear photonic devices: (1) on-chip optical parametric generation sources; (2) broadband Terahertz sources; (3) high-purity photon-pair emitters. These devices will lead to a breakthrough technology to enable highly-integrated, high-efficient and wideband lab-on-chip photonic systems with unprecedented performance in system size, power consumption, flexibility and reliability, ideally fitting numerous growing and emerging applications, e.g. metrology, portable sensing/imaging, and quantum-communications. Based on my proven track record and my pioneering work on 2D materials based photonics and optoelectronics, I believe I will accomplish this ambitious frontier research program with a strong interdisciplinary nature.
Max ERC Funding
2 442 448 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym BioELCell
Project Bioproducts Engineered from Lignocelluloses: from plants and upcycling to next generation materials
Researcher (PI) Orlando Rojas Gaona
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Country Finland
Call Details Advanced Grant (AdG), PE8, ERC-2017-ADG
Summary BioELCell will deliver ground-breaking approaches to create next material generation based on renewable resources, mainly cellulose and lignin micro- and nano-particles (MNC, MNL). Our action will disassemble and re-engineer these plant-based polymers into functional materials that will respond to the demands of the bioeconomy of the future, critically important to Europe and the world. My ambitious, high gain research plan is underpinned in the use of multiphase systems with ultra-low interfacial tension to facilitate nanocellulose liberation and atomization of lignin solution streams into spherical particles.
BioELCell will design novel routes to control MNC and MNL reassembly in new 1-D, 2-D and 3-D structures. The systematic methodologies that I propose will address the main challenges for lignocellulose processing and deployment, considering the important effects of interactions with water. This BioELCell action presents a transformative approach by integrating complementary disciplines that will lead to a far-reaching understanding of lignocellulosic biopolymers and solve key challenges in their use, paving the way to functional product development. Results of this project permeates directly or indirectly in the grand challenges for engineering, namely, water use, carbon sequestration, nitrogen cycle, food and advanced materials. Indeed, after addressing the key fundamental elements of the research lines, BioELCell vindicates such effects based on rational use of plant-based materials as a sustainable resource, making possible the generation of new functions and advanced materials.
BioELCell goes far beyond what is known today about cellulose and lignin micro and nano-particles, some of the most promising materials of our century, which are emerging as key elements for the success of a sustainable society.
Summary
BioELCell will deliver ground-breaking approaches to create next material generation based on renewable resources, mainly cellulose and lignin micro- and nano-particles (MNC, MNL). Our action will disassemble and re-engineer these plant-based polymers into functional materials that will respond to the demands of the bioeconomy of the future, critically important to Europe and the world. My ambitious, high gain research plan is underpinned in the use of multiphase systems with ultra-low interfacial tension to facilitate nanocellulose liberation and atomization of lignin solution streams into spherical particles.
BioELCell will design novel routes to control MNC and MNL reassembly in new 1-D, 2-D and 3-D structures. The systematic methodologies that I propose will address the main challenges for lignocellulose processing and deployment, considering the important effects of interactions with water. This BioELCell action presents a transformative approach by integrating complementary disciplines that will lead to a far-reaching understanding of lignocellulosic biopolymers and solve key challenges in their use, paving the way to functional product development. Results of this project permeates directly or indirectly in the grand challenges for engineering, namely, water use, carbon sequestration, nitrogen cycle, food and advanced materials. Indeed, after addressing the key fundamental elements of the research lines, BioELCell vindicates such effects based on rational use of plant-based materials as a sustainable resource, making possible the generation of new functions and advanced materials.
BioELCell goes far beyond what is known today about cellulose and lignin micro and nano-particles, some of the most promising materials of our century, which are emerging as key elements for the success of a sustainable society.
Max ERC Funding
2 486 182 €
Duration
Start date: 2018-08-01, End date: 2023-07-31
Project acronym BRAIN2BRAIN
Project Towards two-person neuroscience
Researcher (PI) Riitta Kyllikki Hari
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Country Finland
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.
Summary
Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.
Max ERC Funding
2 489 643 €
Duration
Start date: 2009-01-01, End date: 2014-12-31
Project acronym BrainDrain
Project Translational implications of the discovery of brain-draining lymphatics
Researcher (PI) Kari ALITALO
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary In 2010, 800 billion Euros was spent on brain diseases in Europe and the cost is expected to increase due to the aging population. – Here I propose to exploit our new discovery for research to alleviate this disease burden. In work selected by Nature Medicine among the top 10 ”Notable Advances” and by Science as one of the 10 ”Breakthroughs of the year” 2015, we discovered a meningeal lymphatic vascular system that serves brain homeostasis. We want to reassess current concepts about cerebrovascular dynamics, fluid drainage and cellular trafficking in physiological conditions, in Alzheimer’s disease mouse models and in human postmortem tissues. First, we will study the development and properties of meningeal lymphatics and how they are sustained during aging. We then want to analyse the clearance of macromolecules and protein aggregates in Alzheimer’s disease in mice that lack the newly discovered meningeal lymphatic drainage system. We will study if growth factor-mediated expansion of lymphatic vessels alleviates the parenchymal accumulation of neurotoxic amyloid beta and pathogenesis of Alzheimer’s disease and brain damage after traumatic brain injury. We will further analyse the role of lymphangiogenic growth factors and lymphatic vessels in brain solute clearance, immune cell trafficking and in a mouse model of multiple sclerosis. The meningeal lymphatics could be involved in a number of neurodegenerative and neuroinflammatory diseases of considerable human and socioeconomic burden. Several of our previous concepts have already been translated to clinical development and we aim to develop proof-of-principle therapeutic concepts in this project. I feel that we are just now in a unique position to advance frontline European translational biomedical research in this suddenly emerging field, which has received great attention worldwide.
Summary
In 2010, 800 billion Euros was spent on brain diseases in Europe and the cost is expected to increase due to the aging population. – Here I propose to exploit our new discovery for research to alleviate this disease burden. In work selected by Nature Medicine among the top 10 ”Notable Advances” and by Science as one of the 10 ”Breakthroughs of the year” 2015, we discovered a meningeal lymphatic vascular system that serves brain homeostasis. We want to reassess current concepts about cerebrovascular dynamics, fluid drainage and cellular trafficking in physiological conditions, in Alzheimer’s disease mouse models and in human postmortem tissues. First, we will study the development and properties of meningeal lymphatics and how they are sustained during aging. We then want to analyse the clearance of macromolecules and protein aggregates in Alzheimer’s disease in mice that lack the newly discovered meningeal lymphatic drainage system. We will study if growth factor-mediated expansion of lymphatic vessels alleviates the parenchymal accumulation of neurotoxic amyloid beta and pathogenesis of Alzheimer’s disease and brain damage after traumatic brain injury. We will further analyse the role of lymphangiogenic growth factors and lymphatic vessels in brain solute clearance, immune cell trafficking and in a mouse model of multiple sclerosis. The meningeal lymphatics could be involved in a number of neurodegenerative and neuroinflammatory diseases of considerable human and socioeconomic burden. Several of our previous concepts have already been translated to clinical development and we aim to develop proof-of-principle therapeutic concepts in this project. I feel that we are just now in a unique position to advance frontline European translational biomedical research in this suddenly emerging field, which has received great attention worldwide.
Max ERC Funding
2 420 429 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym CleverGenes
Project Novel Gene Therapy Based on the Activation of Endogenous Genes for the Treatment of Ischemia - Concepts of endogenetherapy, release of promoter pausing, promoter-targeted ncRNAs and nuclear RNAi
Researcher (PI) Seppo Ylae-Herttuala
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), LS7, ERC-2014-ADG
Summary Background: Therapeutic angiogenesis with vascular endothelial growth factors (VEGFs) has great potential to become a novel, minimally invasive new treatment for a large number of patients with severe myocardial ischemia. However, this requires development of new technology. Advancing state-of-the-art: We propose a paradigm shift in gene therapy for chronic ischemia by activating endogenous VEGF-A,-B and -C genes and angiogenic transcription programs from the native promoters instead of gene transfer of exogenous cDNA to target tissues. We will develop a new platform technology (endogenetherapy) based on our novel concept of the release of promoter pausing and new promoter-targeted upregulating short hairpinRNAs, tissue-specific superenhancerRNAs activating specific transcription centers involving gene clusters in different chromosomal regions, small circularRNAs formed from self-splicing exons-introns that can be regulated with oligonucleotides and small molecules such as metabolites, nuclear RNAi vectors and specific CRISPR/gRNAmutatedCas9-VP16 technology with an ability to target integration into genomic safe harbor sites. After preclinical studies in mice and in a newly developed chronic cardiac ischemia model in pigs with special emphasis on the analysis of clinically relevant blood flow, metabolic and functional outcomes based on MRI, ultrasound, photoacoustic and PET imaging, the best construct will be taken to a phase I clinical study in patients with severe myocardial ischemia. Since endogenetherapy also involves epigenetic changes, which are reversible and long-lasting, we expect to efficiently activate natural angiogenic programs. Significance: If successful, this approach will begin a new era in gene therapy. Since there is a clear lack of technology capable of targeted upregulation of endogenous genes, the novel endogenetherapy approach may become widely applicable beyond cardiovascular diseases also in other areas of medicine and biomedical research.
Summary
Background: Therapeutic angiogenesis with vascular endothelial growth factors (VEGFs) has great potential to become a novel, minimally invasive new treatment for a large number of patients with severe myocardial ischemia. However, this requires development of new technology. Advancing state-of-the-art: We propose a paradigm shift in gene therapy for chronic ischemia by activating endogenous VEGF-A,-B and -C genes and angiogenic transcription programs from the native promoters instead of gene transfer of exogenous cDNA to target tissues. We will develop a new platform technology (endogenetherapy) based on our novel concept of the release of promoter pausing and new promoter-targeted upregulating short hairpinRNAs, tissue-specific superenhancerRNAs activating specific transcription centers involving gene clusters in different chromosomal regions, small circularRNAs formed from self-splicing exons-introns that can be regulated with oligonucleotides and small molecules such as metabolites, nuclear RNAi vectors and specific CRISPR/gRNAmutatedCas9-VP16 technology with an ability to target integration into genomic safe harbor sites. After preclinical studies in mice and in a newly developed chronic cardiac ischemia model in pigs with special emphasis on the analysis of clinically relevant blood flow, metabolic and functional outcomes based on MRI, ultrasound, photoacoustic and PET imaging, the best construct will be taken to a phase I clinical study in patients with severe myocardial ischemia. Since endogenetherapy also involves epigenetic changes, which are reversible and long-lasting, we expect to efficiently activate natural angiogenic programs. Significance: If successful, this approach will begin a new era in gene therapy. Since there is a clear lack of technology capable of targeted upregulation of endogenous genes, the novel endogenetherapy approach may become widely applicable beyond cardiovascular diseases also in other areas of medicine and biomedical research.
Max ERC Funding
2 437 500 €
Duration
Start date: 2015-11-01, End date: 2021-04-30
Project acronym EPISUSCEPTIBILITY
Project Epigenome and Cancer Susceptibility
Researcher (PI) Paeivi Tuulikki Peltomaeki
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), LS7, ERC-2008-AdG
Summary Early detection is crucial for the outcome of most cancers. Prevention of cancer development is even more desirable. To facilitate these ultimate goals we aim to construct a comprehensive view of the stepwise process through which common human cancers, such as colorectal cancer, arise. In particular, we aim to identify novel mechanisms of cancer susceptibility by focusing on the epigenome, whose alterations may underlie several phenomena related to chronic adult-onset disease that are not explained by genetics alone. The stepwise process of carcinogenesis can be accelerated or halted for various reasons, including inherited susceptibility and diet. The human multi-organ cancer syndromes hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) as well as their murine counterparts, the Mlh1+/- mouse and the ApcMin/+ mouse, will be used as shortcuts to study the interplay between the epigenome and genome in tumorigenesis and to identify biomarkers of cancer susceptibility, malignant transformation, and tumor progression. This will be achieved by molecular profiling of normal and tumor tissues, cell line studies, in vitro functional assays, and in silico approaches. Additionally, the role that the epigenome plays to mediate the effects of the Western type diet on colorectal tumorigenesis will be examined in the mouse. Unlike genetic changes, epigenetic alterations are potentially reversible, which makes them promising targets for preventive and therapeutic interventions.
Summary
Early detection is crucial for the outcome of most cancers. Prevention of cancer development is even more desirable. To facilitate these ultimate goals we aim to construct a comprehensive view of the stepwise process through which common human cancers, such as colorectal cancer, arise. In particular, we aim to identify novel mechanisms of cancer susceptibility by focusing on the epigenome, whose alterations may underlie several phenomena related to chronic adult-onset disease that are not explained by genetics alone. The stepwise process of carcinogenesis can be accelerated or halted for various reasons, including inherited susceptibility and diet. The human multi-organ cancer syndromes hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) as well as their murine counterparts, the Mlh1+/- mouse and the ApcMin/+ mouse, will be used as shortcuts to study the interplay between the epigenome and genome in tumorigenesis and to identify biomarkers of cancer susceptibility, malignant transformation, and tumor progression. This will be achieved by molecular profiling of normal and tumor tissues, cell line studies, in vitro functional assays, and in silico approaches. Additionally, the role that the epigenome plays to mediate the effects of the Western type diet on colorectal tumorigenesis will be examined in the mouse. Unlike genetic changes, epigenetic alterations are potentially reversible, which makes them promising targets for preventive and therapeutic interventions.
Max ERC Funding
2 500 000 €
Duration
Start date: 2009-04-01, End date: 2014-09-30
Project acronym FUTUREGENES
Project Gene transfer techniques in the treatment of cardiovascular diseases and malignant glioma
Researcher (PI) Seppo Yla-Herttuala
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), LS7, ERC-2009-AdG
Summary Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.
Summary
Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.
Max ERC Funding
2 200 000 €
Duration
Start date: 2010-06-01, End date: 2015-05-31
Project acronym HeartGenes
Project Next Generation Gene Therapy for the Treatment of Chronic Myocardial Ischemia and Heart Failure
Researcher (PI) Seppo YLae-HERTTUALA
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), LS7, ERC-2019-ADG
Summary BACKGROUND: Therapeutic angiogenesis has great potential for the treatment of severe heart diseases. However, this requires novel approaches and development of new technology.
ADVANCING STATE-OF-THE-ART: We will develop novel VEGF-B and VEGF-C-based gene therapy to treat refractory angina and heart failure (HF). VEGF-B and VEGF-C lead factors were selected from extensive pig studies where they showed the best benefits among all VEGFs, such as relative cardiac specificity, potent angiogenic and metabolic effects (VEGF-B) and lymphangiogenic activity (VEGF-C). Exogenous gene transfer and new endogenous gene activation technology will be developed.
Key new technologies are riboswitch-regulated-AAV8 vectors, Super-Enhancer driven cell-type targeted gene expression, VEGF-B and VEGF-C designer mutants for better efficacy and activation of natural endogenous VEGF-B and VEGF-C expression with promoter binding shRNAs, circRNAs, CRISPR/mutantCas9-VP64-SAM gene activation technology and using a novel concept of the release of promoter pausing. Immunological concerns of AAV8 and usefulness of new synthetic dendrimer carriers will be addressed.
HeartGenes utilizes optimized percutaneous intramyocardial and retrograde venous gene delivery in pig chronic ischemia and HF models, clinically relevant pig exercise test, and 15O-H2O and 18F-FDG PET/MRI imaging to detect treatment effects.
Simultaneously, HeartGenes will take a realistic approach to clinical translation and starts intramyocardial vs retrograde venous riboswitch-AAV8-VEGF-B186 phase I trial in refractory angina as the first step to bring the best novel constructs and the most advanced functional and imaging endpoints developed in HeartGenes to clinical testing at the end of the project.
SIGNIFICANCE: If successful, this approach will bring a paradigm shift to cardiac gene therapy and new therapeutic options for heart diseases. Novel new technologies may also become widely applicable in other areas of medicine.
Summary
BACKGROUND: Therapeutic angiogenesis has great potential for the treatment of severe heart diseases. However, this requires novel approaches and development of new technology.
ADVANCING STATE-OF-THE-ART: We will develop novel VEGF-B and VEGF-C-based gene therapy to treat refractory angina and heart failure (HF). VEGF-B and VEGF-C lead factors were selected from extensive pig studies where they showed the best benefits among all VEGFs, such as relative cardiac specificity, potent angiogenic and metabolic effects (VEGF-B) and lymphangiogenic activity (VEGF-C). Exogenous gene transfer and new endogenous gene activation technology will be developed.
Key new technologies are riboswitch-regulated-AAV8 vectors, Super-Enhancer driven cell-type targeted gene expression, VEGF-B and VEGF-C designer mutants for better efficacy and activation of natural endogenous VEGF-B and VEGF-C expression with promoter binding shRNAs, circRNAs, CRISPR/mutantCas9-VP64-SAM gene activation technology and using a novel concept of the release of promoter pausing. Immunological concerns of AAV8 and usefulness of new synthetic dendrimer carriers will be addressed.
HeartGenes utilizes optimized percutaneous intramyocardial and retrograde venous gene delivery in pig chronic ischemia and HF models, clinically relevant pig exercise test, and 15O-H2O and 18F-FDG PET/MRI imaging to detect treatment effects.
Simultaneously, HeartGenes will take a realistic approach to clinical translation and starts intramyocardial vs retrograde venous riboswitch-AAV8-VEGF-B186 phase I trial in refractory angina as the first step to bring the best novel constructs and the most advanced functional and imaging endpoints developed in HeartGenes to clinical testing at the end of the project.
SIGNIFICANCE: If successful, this approach will bring a paradigm shift to cardiac gene therapy and new therapeutic options for heart diseases. Novel new technologies may also become widely applicable in other areas of medicine.
Max ERC Funding
2 500 000 €
Duration
Start date: 2021-05-01, End date: 2026-04-30
