Project acronym AGNES
Project ACTIVE AGEING – RESILIENCE AND EXTERNAL SUPPORT AS MODIFIERS OF THE DISABLEMENT OUTCOME
Researcher (PI) Taina Tuulikki RANTANEN
Host Institution (HI) JYVASKYLAN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), SH3, ERC-2015-AdG
Summary The goals are 1. To develop a scale assessing the diversity of active ageing with four dimensions that are ability (what people can do), activity (what people do do), ambition (what are the valued activities that people want to do), and autonomy (how satisfied people are with the opportunity to do valued activities); 2. To examine health and physical and psychological functioning as the determinants and social and build environment, resilience and personal skills as modifiers of active ageing; 3. To develop a multicomponent sustainable intervention aiming to promote active ageing (methods: counselling, information technology, help from volunteers); 4. To test the feasibility and effectiveness on the intervention; and 5. To study cohort effects on the phenotypes on the pathway to active ageing.
“If You Can Measure It, You Can Change It.” Active ageing assessment needs conceptual progress, which I propose to do. A quantifiable scale will be developed that captures the diversity of active ageing stemming from the WHO definition of active ageing as the process of optimizing opportunities for health and participation in the society for all people in line with their needs, goals and capacities as they age. I will collect cross-sectional data (N=1000, ages 75, 80 and 85 years) and model the pathway to active ageing with state-of-the art statistical methods. By doing this I will create novel knowledge on preconditions for active ageing. The collected cohort data will be compared to a pre-existing cohort data that was collected 25 years ago to obtain knowledge about changes over time in functioning of older people. A randomized controlled trial (N=200) will be conducted to assess the effectiveness of the envisioned intervention promoting active ageing through participation. The project will regenerate ageing research by launching a novel scale, by training young scientists, by creating new concepts and theory development and by producing evidence for active ageing promotion
Summary
The goals are 1. To develop a scale assessing the diversity of active ageing with four dimensions that are ability (what people can do), activity (what people do do), ambition (what are the valued activities that people want to do), and autonomy (how satisfied people are with the opportunity to do valued activities); 2. To examine health and physical and psychological functioning as the determinants and social and build environment, resilience and personal skills as modifiers of active ageing; 3. To develop a multicomponent sustainable intervention aiming to promote active ageing (methods: counselling, information technology, help from volunteers); 4. To test the feasibility and effectiveness on the intervention; and 5. To study cohort effects on the phenotypes on the pathway to active ageing.
“If You Can Measure It, You Can Change It.” Active ageing assessment needs conceptual progress, which I propose to do. A quantifiable scale will be developed that captures the diversity of active ageing stemming from the WHO definition of active ageing as the process of optimizing opportunities for health and participation in the society for all people in line with their needs, goals and capacities as they age. I will collect cross-sectional data (N=1000, ages 75, 80 and 85 years) and model the pathway to active ageing with state-of-the art statistical methods. By doing this I will create novel knowledge on preconditions for active ageing. The collected cohort data will be compared to a pre-existing cohort data that was collected 25 years ago to obtain knowledge about changes over time in functioning of older people. A randomized controlled trial (N=200) will be conducted to assess the effectiveness of the envisioned intervention promoting active ageing through participation. The project will regenerate ageing research by launching a novel scale, by training young scientists, by creating new concepts and theory development and by producing evidence for active ageing promotion
Max ERC Funding
2 044 364 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym ALPHA
Project Alpha Shape Theory Extended
Researcher (PI) Herbert Edelsbrunner
Host Institution (HI) INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA
Country Austria
Call Details Advanced Grant (AdG), PE6, ERC-2017-ADG
Summary Alpha shapes were invented in the early 80s of last century, and their implementation in three dimensions in the early 90s was at the forefront of the exact arithmetic paradigm that enabled fast and correct geometric software. In the late 90s, alpha shapes motivated the development of the wrap algorithm for surface reconstruction, and of persistent homology, which was the starting point of rapidly expanding interest in topological algorithms aimed at data analysis questions.
We now see alpha shapes, wrap complexes, and persistent homology as three aspects of a larger theory, which we propose to fully develop. This viewpoint was a long time coming and finds its clear expression within a generalized
version of discrete Morse theory. This unified framework offers new opportunities, including
(I) the adaptive reconstruction of shapes driven by the cavity structure;
(II) the stochastic analysis of all aspects of the theory;
(III) the computation of persistence of dense data, both in scale and in depth;
(IV) the study of long-range order in periodic and near-periodic point configurations.
These capabilities will significantly deepen as well as widen the theory and enable new applications in the sciences. To gain focus, we concentrate on low-dimensional applications in structural molecular biology and particle systems.
Summary
Alpha shapes were invented in the early 80s of last century, and their implementation in three dimensions in the early 90s was at the forefront of the exact arithmetic paradigm that enabled fast and correct geometric software. In the late 90s, alpha shapes motivated the development of the wrap algorithm for surface reconstruction, and of persistent homology, which was the starting point of rapidly expanding interest in topological algorithms aimed at data analysis questions.
We now see alpha shapes, wrap complexes, and persistent homology as three aspects of a larger theory, which we propose to fully develop. This viewpoint was a long time coming and finds its clear expression within a generalized
version of discrete Morse theory. This unified framework offers new opportunities, including
(I) the adaptive reconstruction of shapes driven by the cavity structure;
(II) the stochastic analysis of all aspects of the theory;
(III) the computation of persistence of dense data, both in scale and in depth;
(IV) the study of long-range order in periodic and near-periodic point configurations.
These capabilities will significantly deepen as well as widen the theory and enable new applications in the sciences. To gain focus, we concentrate on low-dimensional applications in structural molecular biology and particle systems.
Max ERC Funding
1 678 432 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym ARCHADAPT
Project The architecture of adaptation to novel environments
Researcher (PI) Christian Werner Schloetterer
Host Institution (HI) VETERINAERMEDIZINISCHE UNIVERSITAET WIEN
Country Austria
Call Details Advanced Grant (AdG), LS8, ERC-2011-ADG_20110310
Summary One of the central goals in evolutionary biology is to understand adaptation. Experimental evolution represents a highly promising approach to study adaptation. In this proposal, a freshly collected D. simulans population will be allowed to adapt to laboratory conditions under two different temperature regimes: hot (27°C) and cold (18°C). The trajectories of adaptation to these novel environments will be monitored on three levels: 1) genomic, 2) transcriptomic, 3) phenotypic. Allele frequency changes during the experiment will be measured by next generation sequencing of DNA pools (Pool-Seq) to identify targets of selection. RNA-Seq will be used to trace adaptation on the transcriptomic level during three developmental stages. Eight different phenotypes will be scored to measure the phenotypic consequences of adaptation. Combining the adaptive trajectories on these three levels will provide a picture of adaptation for a multicellular, outcrossing organism that is far more detailed than any previous results.
Furthermore, the proposal addresses the question of how adaptation on these three levels is reversible if the environment reverts to ancestral conditions. The third aspect of adaptation covered in the proposal is the question of repeatability of adaptation. Again, this question will be addressed on the three levels: genomic, transcriptomic and phenotypic. Using replicates with different degrees of genetic similarity, as well as closely related species, we will test how similar the adaptive response is.
This large-scale study will provide new insights into the importance of standing variation for the adaptation to novel environments. Hence, apart from providing significant evolutionary insights on the trajectories of adaptation, the results we will obtain will have important implications for conservation genetics and commercial breeding.
Summary
One of the central goals in evolutionary biology is to understand adaptation. Experimental evolution represents a highly promising approach to study adaptation. In this proposal, a freshly collected D. simulans population will be allowed to adapt to laboratory conditions under two different temperature regimes: hot (27°C) and cold (18°C). The trajectories of adaptation to these novel environments will be monitored on three levels: 1) genomic, 2) transcriptomic, 3) phenotypic. Allele frequency changes during the experiment will be measured by next generation sequencing of DNA pools (Pool-Seq) to identify targets of selection. RNA-Seq will be used to trace adaptation on the transcriptomic level during three developmental stages. Eight different phenotypes will be scored to measure the phenotypic consequences of adaptation. Combining the adaptive trajectories on these three levels will provide a picture of adaptation for a multicellular, outcrossing organism that is far more detailed than any previous results.
Furthermore, the proposal addresses the question of how adaptation on these three levels is reversible if the environment reverts to ancestral conditions. The third aspect of adaptation covered in the proposal is the question of repeatability of adaptation. Again, this question will be addressed on the three levels: genomic, transcriptomic and phenotypic. Using replicates with different degrees of genetic similarity, as well as closely related species, we will test how similar the adaptive response is.
This large-scale study will provide new insights into the importance of standing variation for the adaptation to novel environments. Hence, apart from providing significant evolutionary insights on the trajectories of adaptation, the results we will obtain will have important implications for conservation genetics and commercial breeding.
Max ERC Funding
2 452 084 €
Duration
Start date: 2012-07-01, End date: 2018-06-30
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 CDK6-DrugOpp
Project CDK6 in transcription - turning a foe in a friend
Researcher (PI) Veronika SEXL
Host Institution (HI) VETERINAERMEDIZINISCHE UNIVERSITAET WIEN
Country Austria
Call Details Advanced Grant (AdG), LS7, ERC-2015-AdG
Summary "Translational research aims at applying mechanistic understanding in the development of "precision medicine", which depends on precise diagnostic tools and therapeutic approaches. Cancer therapy is experiencing a switch from non-specific, cytotoxic agents towards molecularly targeted and rationally designed compounds with the promise of greater efficacy and fewer side effects.
The two cell-cycle kinases CDK4 and CDK6 normally facilitate cell-cycle progression but are abnormally activated in certain cancers. CDK6 is up-regulated in hematopoietic malignancies, where it is the predominant cell-cycle kinase. The importance of CDK4/6 for tumor development is underscored by the fact that the US FDA selected inhibitors of the kinase activity of CDK4/6 as "breakthrough of the year 2013". Our recent findings suggest that the effects of the inhibitors may be limited as CDK6 is not only involved in cell-cycle progression: ground-breaking research in my group and others has shown that CDK6 is involved in regulation of transcription in a kinase-independent manner thereby driving the proliferation of leukemic stem cells and tumor formation. We have now identified mutations in CDK6 that convert it from a tumor promoter into a tumor suppressor. This unexpected outcome is accompanied by a distinct transcriptional profile. Separating the tumor-promoting from the tumor suppressive functions may open a novel therapeutic avenue for drug development. We aim at understanding which domains and residues of CDK6 are involved in rewiring the transcriptional landscape to pave the way for sophisticated inhibitors. The idea of turning a cancer cell's own most potent weapon against itself is novel and would represent a new paradigm for drug design. Finally, the understanding of CDK6 functions in tumor promotion and maintenance will also result in better patient stratification and improved treatment decisions for a broad spectrum of cancer types."
Summary
"Translational research aims at applying mechanistic understanding in the development of "precision medicine", which depends on precise diagnostic tools and therapeutic approaches. Cancer therapy is experiencing a switch from non-specific, cytotoxic agents towards molecularly targeted and rationally designed compounds with the promise of greater efficacy and fewer side effects.
The two cell-cycle kinases CDK4 and CDK6 normally facilitate cell-cycle progression but are abnormally activated in certain cancers. CDK6 is up-regulated in hematopoietic malignancies, where it is the predominant cell-cycle kinase. The importance of CDK4/6 for tumor development is underscored by the fact that the US FDA selected inhibitors of the kinase activity of CDK4/6 as "breakthrough of the year 2013". Our recent findings suggest that the effects of the inhibitors may be limited as CDK6 is not only involved in cell-cycle progression: ground-breaking research in my group and others has shown that CDK6 is involved in regulation of transcription in a kinase-independent manner thereby driving the proliferation of leukemic stem cells and tumor formation. We have now identified mutations in CDK6 that convert it from a tumor promoter into a tumor suppressor. This unexpected outcome is accompanied by a distinct transcriptional profile. Separating the tumor-promoting from the tumor suppressive functions may open a novel therapeutic avenue for drug development. We aim at understanding which domains and residues of CDK6 are involved in rewiring the transcriptional landscape to pave the way for sophisticated inhibitors. The idea of turning a cancer cell's own most potent weapon against itself is novel and would represent a new paradigm for drug design. Finally, the understanding of CDK6 functions in tumor promotion and maintenance will also result in better patient stratification and improved treatment decisions for a broad spectrum of cancer types."
Max ERC Funding
2 497 520 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym CHALLENGE
Project Persistent bullying cases: towards tailored intervention approaches to maximize efficiency
Researcher (PI) Christina SALMIVALLI
Host Institution (HI) TURUN YLIOPISTO
Country Finland
Call Details Advanced Grant (AdG), SH3, ERC-2019-ADG
Summary Bullying in schools is widespread, with adverse effects on youth and high costs for societies. Research on bullying prevention has so far focused on average effects of anti-bullying programs and mainly concerned universal, preventive measures. While important, this has overshadowed attempts to uncover how exactly school personnel intervene in particular bullying cases and when and why that fails. CHALLENGE will open up new research horizons by shifting the focus from average program effects to the characteristics and conditions of youth who remain victimized or continue bullying despite targeted interventions. The next big questions in the field are tackled in four work packages:
WP1 uncovers the key features of persistent bullying, such as the extent to which it is due to school-level factors or rather varies across bullying cases (within schools).
WP2 elucidates the plight of persistent victims by testing why victimized youth are most maladjusted in contexts where the overall level of victimization is decreasing (healthy context paradox, Garandeau & Salmivalli, 2019).
WP3 tests the efficacy of different targeted interventions in real-life conditions, uncovering challenge factors that increase the risk of a bullying case remaining unresolved. Moreover, it tests how youth characteristics affect their cognitive, emotional and motivational responses to different interventions.
WP4 utilizes molecular genetics to test genetic susceptibility to intervention effects at the individual level.
CHALLENGE uses quantitative, qualitative, and DNA analyses, combines longitudinal and experimental designs, and harnesses novel tools to collect real-time intervention data and to register children’s responses to interventions. It bridges the perspectives of developmental and social psychology, child psychiatry, and genetics, builds theory on persistent bullying and enables the development of tailored measures for specific target groups where available interventions have failed
Summary
Bullying in schools is widespread, with adverse effects on youth and high costs for societies. Research on bullying prevention has so far focused on average effects of anti-bullying programs and mainly concerned universal, preventive measures. While important, this has overshadowed attempts to uncover how exactly school personnel intervene in particular bullying cases and when and why that fails. CHALLENGE will open up new research horizons by shifting the focus from average program effects to the characteristics and conditions of youth who remain victimized or continue bullying despite targeted interventions. The next big questions in the field are tackled in four work packages:
WP1 uncovers the key features of persistent bullying, such as the extent to which it is due to school-level factors or rather varies across bullying cases (within schools).
WP2 elucidates the plight of persistent victims by testing why victimized youth are most maladjusted in contexts where the overall level of victimization is decreasing (healthy context paradox, Garandeau & Salmivalli, 2019).
WP3 tests the efficacy of different targeted interventions in real-life conditions, uncovering challenge factors that increase the risk of a bullying case remaining unresolved. Moreover, it tests how youth characteristics affect their cognitive, emotional and motivational responses to different interventions.
WP4 utilizes molecular genetics to test genetic susceptibility to intervention effects at the individual level.
CHALLENGE uses quantitative, qualitative, and DNA analyses, combines longitudinal and experimental designs, and harnesses novel tools to collect real-time intervention data and to register children’s responses to interventions. It bridges the perspectives of developmental and social psychology, child psychiatry, and genetics, builds theory on persistent bullying and enables the development of tailored measures for specific target groups where available interventions have failed
Max ERC Funding
2 424 001 €
Duration
Start date: 2020-10-01, End date: 2025-09-30
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 CohesinMolMech
Project Molecular mechanisms of cohesin-mediated sister chromatid cohesion and chromatin organization
Researcher (PI) Jan-Michael Peters
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Country Austria
Call Details Advanced Grant (AdG), LS1, ERC-2015-AdG
Summary During S-phase newly synthesized “sister” DNA molecules become physically connected. This sister chromatid cohesion resists the pulling forces of the mitotic spindle and thereby enables the bi-orientation and subsequent symmetrical segregation of chromosomes. Cohesion is mediated by ring-shaped cohesin complexes, which are thought to entrap sister DNA molecules topologically. In mammalian cells, cohesin is loaded onto DNA at the end of mitosis by the Scc2-Scc4 complex, becomes acetylated during S-phase, and is stably “locked” on DNA during S- and G2-phase by sororin. Sororin stabilizes cohesin on DNA by inhibiting Wapl, which can otherwise release cohesin from DNA again. In addition to mediating cohesion, cohesin also has important roles in organizing higher-order chromatin structures and in gene regulation. Cohesin performs the latter functions in both proliferating and post-mitotic cells and mediates at least some of these together with the sequence-specific DNA-binding protein CTCF, which co-localizes with cohesin at many genomic sites. Although cohesin and CTCF perform essential functions in mammalian cells, it is poorly understood how cohesin is loaded onto DNA by Scc2-Scc4, how cohesin is positioned in the genome, how cohesin is released from DNA again by Wapl, and how Wapl is inhibited by sororin. Likewise, it is not known how cohesin establishes cohesion during DNA replication and how cohesin cooperates with CTCF to organize chromatin structure. Here we propose to address these questions by combining biochemical reconstitution, single-molecule TIRF microscopy, genetic and cell biological approaches. We expect that the results of these studies will advance our understanding of cell division, chromatin structure and gene regulation, and may also provide insight into the etiology of disorders that are caused by cohesin dysfunction, such as Down syndrome and “cohesinopathies” or cancers, in which cohesin mutations have been found to occur frequently.
Summary
During S-phase newly synthesized “sister” DNA molecules become physically connected. This sister chromatid cohesion resists the pulling forces of the mitotic spindle and thereby enables the bi-orientation and subsequent symmetrical segregation of chromosomes. Cohesion is mediated by ring-shaped cohesin complexes, which are thought to entrap sister DNA molecules topologically. In mammalian cells, cohesin is loaded onto DNA at the end of mitosis by the Scc2-Scc4 complex, becomes acetylated during S-phase, and is stably “locked” on DNA during S- and G2-phase by sororin. Sororin stabilizes cohesin on DNA by inhibiting Wapl, which can otherwise release cohesin from DNA again. In addition to mediating cohesion, cohesin also has important roles in organizing higher-order chromatin structures and in gene regulation. Cohesin performs the latter functions in both proliferating and post-mitotic cells and mediates at least some of these together with the sequence-specific DNA-binding protein CTCF, which co-localizes with cohesin at many genomic sites. Although cohesin and CTCF perform essential functions in mammalian cells, it is poorly understood how cohesin is loaded onto DNA by Scc2-Scc4, how cohesin is positioned in the genome, how cohesin is released from DNA again by Wapl, and how Wapl is inhibited by sororin. Likewise, it is not known how cohesin establishes cohesion during DNA replication and how cohesin cooperates with CTCF to organize chromatin structure. Here we propose to address these questions by combining biochemical reconstitution, single-molecule TIRF microscopy, genetic and cell biological approaches. We expect that the results of these studies will advance our understanding of cell division, chromatin structure and gene regulation, and may also provide insight into the etiology of disorders that are caused by cohesin dysfunction, such as Down syndrome and “cohesinopathies” or cancers, in which cohesin mutations have been found to occur frequently.
Max ERC Funding
2 500 000 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym COMBINE
Project From flies to humans combining whole genome screens and tissue specific gene targeting to identify novel pathways involved in cancer and metastases
Researcher (PI) Josef Martin Penninger
Host Institution (HI) INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Country Austria
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Cancer care will be revolutionized over the next decade by the introduction of novel therapeutics that target the underlying molecular mechanisms of the disease. With the advent of human genetics, a plethora of genes have been correlated with human diseases such as cancer the SNP maps. Since the sequences are now available, the next big challenge is to determine the function of these genes in the context of the entire organism. Genetic animal models have proven to be extremely valuable to elucidate the essential functions of genes in normal physiology and the pathogenesis of disease. Using gene-targeted mice we have previously identified RANKL as a master gene of bone loss in arthritis, osteoporosis, and cancer cell migration and metastases and genes that control heart and kidney function; wound healing; diabetes; or lung injury Our primary goal is to use functional genomics in Drosophila and mice to understand cell transformation, invasion, and cancer metastases of epithelial tumors. The following projects are proposed: 1. Role of the key osteoclast differentiation factors RANKL-RANK and its downstream signalling cascade in the development of breast and prostate cancer. 2. Requirement of osteoclasts for bone metastases and stem cell niches using a new RANKfloxed allele; function of RANKL-RANK in local tumor cell invasion. 3. Role of RANKL-RANK in the central fever response to understand potential implications of future RANKL-RANK directed therapies. 4. Integration of gene targeting in mice with state-of-the art technologies in fly genetics; use of whole genome tissue-specific in vivo RNAi Drosophila libraries to identify essential and novel pathways for cancer pathogenesis using whole genome screens. 5. Role of TSPAN6, as a candidate lung metastasis gene. Identification of new cancer disease genes will allow us to design novel strategies for cancer treatment and will have ultimately impact on the basic understanding of cancer, metastases, and human health.
Summary
Cancer care will be revolutionized over the next decade by the introduction of novel therapeutics that target the underlying molecular mechanisms of the disease. With the advent of human genetics, a plethora of genes have been correlated with human diseases such as cancer the SNP maps. Since the sequences are now available, the next big challenge is to determine the function of these genes in the context of the entire organism. Genetic animal models have proven to be extremely valuable to elucidate the essential functions of genes in normal physiology and the pathogenesis of disease. Using gene-targeted mice we have previously identified RANKL as a master gene of bone loss in arthritis, osteoporosis, and cancer cell migration and metastases and genes that control heart and kidney function; wound healing; diabetes; or lung injury Our primary goal is to use functional genomics in Drosophila and mice to understand cell transformation, invasion, and cancer metastases of epithelial tumors. The following projects are proposed: 1. Role of the key osteoclast differentiation factors RANKL-RANK and its downstream signalling cascade in the development of breast and prostate cancer. 2. Requirement of osteoclasts for bone metastases and stem cell niches using a new RANKfloxed allele; function of RANKL-RANK in local tumor cell invasion. 3. Role of RANKL-RANK in the central fever response to understand potential implications of future RANKL-RANK directed therapies. 4. Integration of gene targeting in mice with state-of-the art technologies in fly genetics; use of whole genome tissue-specific in vivo RNAi Drosophila libraries to identify essential and novel pathways for cancer pathogenesis using whole genome screens. 5. Role of TSPAN6, as a candidate lung metastasis gene. Identification of new cancer disease genes will allow us to design novel strategies for cancer treatment and will have ultimately impact on the basic understanding of cancer, metastases, and human health.
Max ERC Funding
2 499 465 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
