Project acronym BIOMOL. SIMULATION
Project Development of multi-scale molecular models, force fields and computer software for biomolecular simulation
Researcher (PI) Willem Frederik Van Gunsteren
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Advanced Grant (AdG), PE4, ERC-2008-AdG
Summary During the past decades the PI has helped shape the research field of computer simulation of biomolecular systems at the atomic level. He has carried out one of the first molecular dynamics (MD) simulations of proteins, and has since then contributed many different methodological improvements and developed one of the major atomic-level force fields for simulations of proteins, carbohydrates, nucleotides and lipids. Methodology and force field have been implemented in a set of programs called GROMOS (GROningen MOlecular Simulation package), which is currently used in hundreds of academic and industrial research groups from over 50 countries on all continents. It is proposed to develop a next generation of molecular models, force fields, multi-scaling simulation methodology and software for biomolecular simulations which is at least an order of magnitude more accurate in terms of energetics, and which is 1000 times more efficient through the use of coarse-grained molecular models than the currently available software and models.
Summary
During the past decades the PI has helped shape the research field of computer simulation of biomolecular systems at the atomic level. He has carried out one of the first molecular dynamics (MD) simulations of proteins, and has since then contributed many different methodological improvements and developed one of the major atomic-level force fields for simulations of proteins, carbohydrates, nucleotides and lipids. Methodology and force field have been implemented in a set of programs called GROMOS (GROningen MOlecular Simulation package), which is currently used in hundreds of academic and industrial research groups from over 50 countries on all continents. It is proposed to develop a next generation of molecular models, force fields, multi-scaling simulation methodology and software for biomolecular simulations which is at least an order of magnitude more accurate in terms of energetics, and which is 1000 times more efficient through the use of coarse-grained molecular models than the currently available software and models.
Max ERC Funding
1 320 000 €
Duration
Start date: 2008-11-01, End date: 2014-09-30
Project acronym BIOMOLECULAR_COMP
Project Biomolecular computers
Researcher (PI) Ehud Shapiro
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS9, ERC-2008-AdG
Summary Autonomous programmable computing devices made of biological molecules hold the promise of interacting with the biological environment in future biological and medical applications. Our laboratory's long-term objective is to develop a 'Doctor in a cell': molecular-sized device that can roam the body, equipped with medical knowledge. It would diagnose a disease by analyzing the data available in its biochemical environment based on the encoded medical knowledge and treat it by releasing the appropriate drug molecule in situ. This kind of device might, in the future, be delivered to all cells in a specific tissue, organ or the whole organism, and cure or kill only those cells diagnosed with a disease. Our laboratory embarked on the attempt to design and build these molecular computing devices and lay the foundation for their future biomedical applications. Several important milestones have already been accomplished towards the realization of the Doctor in a cell vision. The subject of this proposal is a construction of autonomous biomolecular computers that could be delivered into a living cell, interact with endogenous biomolecules that are known to indicate diseases, logically analyze them, make a diagnostic decision and couple it to the production of an active biomolecule capable of influencing cell fate.
Summary
Autonomous programmable computing devices made of biological molecules hold the promise of interacting with the biological environment in future biological and medical applications. Our laboratory's long-term objective is to develop a 'Doctor in a cell': molecular-sized device that can roam the body, equipped with medical knowledge. It would diagnose a disease by analyzing the data available in its biochemical environment based on the encoded medical knowledge and treat it by releasing the appropriate drug molecule in situ. This kind of device might, in the future, be delivered to all cells in a specific tissue, organ or the whole organism, and cure or kill only those cells diagnosed with a disease. Our laboratory embarked on the attempt to design and build these molecular computing devices and lay the foundation for their future biomedical applications. Several important milestones have already been accomplished towards the realization of the Doctor in a cell vision. The subject of this proposal is a construction of autonomous biomolecular computers that could be delivered into a living cell, interact with endogenous biomolecules that are known to indicate diseases, logically analyze them, make a diagnostic decision and couple it to the production of an active biomolecule capable of influencing cell fate.
Max ERC Funding
2 125 980 €
Duration
Start date: 2009-01-01, End date: 2013-10-31
Project acronym BONE SCAN
Project Traces in the bones: reconstructing the lost soft anatomy of the earliest vertebrates through ultra-high resolution synchrotron scanning
Researcher (PI) Per Erik Ahlberg
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Advanced Grant (AdG), LS8, ERC-2008-AdG
Summary Early vertebrate evolution involved a series of drastic structural reorganisations as new features were added and elaborated. The fossil record illuminates this evolutionary history more directly than inferences from the diversity of living forms, but the fossils usually consist only of bones whereas many of the most important and interesting changes occurred in the soft anatomy. Traditional approaches to reconstructing the musculature and other soft tissues of fossil vertebrates rely on subjective tools, like the visual identification of rough bone textures thought to indicate muscle attachments, and generally leave a lot to be desired. Here I propose a wholly novel and radically more objective approach to the identification of soft-tissue contacts, using holotomographic synchrotron CT at sub-micron resolutions to identify these contacts by the three-dimensional micro-architecture of the bone. A pilot study has already shown that such scans (performed at the ESRF synchrotron facility in Grenoble) are capable of imaging key features such as arrested growth surfaces and probable Sharpey s fibres in 380 million year old fossils. We will undertake a systematic review of the three-dimensional bone micro-architectures associated with different soft-tissue contacts in living vertebrates, and the use this as a key to reconstruct the soft-tissue contacts on fossil bones with unprecedented accuracy. This will permit us to produce far more reliable reconstructions of the soft anatomy than has hitherto been possible. Our findings will inform other areas of palaentology, particularly functional morphology, and will also be of great importance to evolutionary developmental biology.
Summary
Early vertebrate evolution involved a series of drastic structural reorganisations as new features were added and elaborated. The fossil record illuminates this evolutionary history more directly than inferences from the diversity of living forms, but the fossils usually consist only of bones whereas many of the most important and interesting changes occurred in the soft anatomy. Traditional approaches to reconstructing the musculature and other soft tissues of fossil vertebrates rely on subjective tools, like the visual identification of rough bone textures thought to indicate muscle attachments, and generally leave a lot to be desired. Here I propose a wholly novel and radically more objective approach to the identification of soft-tissue contacts, using holotomographic synchrotron CT at sub-micron resolutions to identify these contacts by the three-dimensional micro-architecture of the bone. A pilot study has already shown that such scans (performed at the ESRF synchrotron facility in Grenoble) are capable of imaging key features such as arrested growth surfaces and probable Sharpey s fibres in 380 million year old fossils. We will undertake a systematic review of the three-dimensional bone micro-architectures associated with different soft-tissue contacts in living vertebrates, and the use this as a key to reconstruct the soft-tissue contacts on fossil bones with unprecedented accuracy. This will permit us to produce far more reliable reconstructions of the soft anatomy than has hitherto been possible. Our findings will inform other areas of palaentology, particularly functional morphology, and will also be of great importance to evolutionary developmental biology.
Max ERC Funding
1 046 782 €
Duration
Start date: 2009-04-01, End date: 2014-03-31
Project acronym BRAIN2BRAIN
Project Towards two-person neuroscience
Researcher (PI) Riitta Kyllikki Hari
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
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 BRIO
Project Bounded Rationality in Industrial Organization
Researcher (PI) Ran Spiegler
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), SH1, ERC-2008-AdG
Summary "Economists' modern understanding of the functioning of markets is based on the behavioral assumption of individual rationality. Market agents are assumed to hold well-defined preferences and have perfect ability to draw Bayesian inferences in accordance with correct knowledge of the market model and market equilibrium. This research proposal is based on the premise that bounded rationality on the part of consumers is potentially a major source of market friction. My objective is to develop general theoretical tools to investigate this intuition, and to examine whether these tools can be insightfully applied to realistic market settings. So far, the literature on the subject has progressed as a sequence of specific models that capture one aspect of consumer psychology at a time. The challenge is to synthesize and generalize these models into flexible theoretical frameworks for modelling market interaction between profit-maximizing firms and boundedly rational consumers. Hopefully, various aspects of consumer psychology can be embedded into these frameworks, so that analytic results can be stated in terms of general, abstract properties of consumer behavior, rather than in terms of specific psychological effects. In turn, this general analysis is expected to lead to novel applications. Here are some of the general questions that I hope to address. Can we view certain aspects of firms' pricing and marketing strategies as responses to consumers' bounded rationality? To what extent are boundedly rational consumers vulnerable to exploitation by firms? Does competition protect them from exploitation? Does interaction between firms and boundedly rational consumers give rise to inefficiencies, and how are these affected by competition? What is the impact of various regulatory interventions in this context? Do market forces lead firms to ""educate"" or ""debias"" boundedly rational consumers? Does greater consumer rationality imply more competitive industry profits?"
Summary
"Economists' modern understanding of the functioning of markets is based on the behavioral assumption of individual rationality. Market agents are assumed to hold well-defined preferences and have perfect ability to draw Bayesian inferences in accordance with correct knowledge of the market model and market equilibrium. This research proposal is based on the premise that bounded rationality on the part of consumers is potentially a major source of market friction. My objective is to develop general theoretical tools to investigate this intuition, and to examine whether these tools can be insightfully applied to realistic market settings. So far, the literature on the subject has progressed as a sequence of specific models that capture one aspect of consumer psychology at a time. The challenge is to synthesize and generalize these models into flexible theoretical frameworks for modelling market interaction between profit-maximizing firms and boundedly rational consumers. Hopefully, various aspects of consumer psychology can be embedded into these frameworks, so that analytic results can be stated in terms of general, abstract properties of consumer behavior, rather than in terms of specific psychological effects. In turn, this general analysis is expected to lead to novel applications. Here are some of the general questions that I hope to address. Can we view certain aspects of firms' pricing and marketing strategies as responses to consumers' bounded rationality? To what extent are boundedly rational consumers vulnerable to exploitation by firms? Does competition protect them from exploitation? Does interaction between firms and boundedly rational consumers give rise to inefficiencies, and how are these affected by competition? What is the impact of various regulatory interventions in this context? Do market forces lead firms to ""educate"" or ""debias"" boundedly rational consumers? Does greater consumer rationality imply more competitive industry profits?"
Max ERC Funding
1 098 637 €
Duration
Start date: 2008-11-01, End date: 2014-10-31
Project acronym BRSCDP-TEA
Project Bounded rationality and social concerns in decision processes: theory, experiments, and applications
Researcher (PI) Massimo Marinacci
Host Institution (HI) UNIVERSITA COMMERCIALE LUIGI BOCCONI
Call Details Advanced Grant (AdG), SH1, ERC-2008-AdG
Summary In the field of economics, individual decision making is the basic building block for studying complex environments such as markets, political systems, and social dynamics. Individual decision making is embodied in the neoclassical economically rational agent, whose only concern is the maximization of utility from his own material consumption. Two qualities of this agent are especially important for the research we will undertake: He has perfect understanding of the problems he faces - today and in the future - and unbounded computational ability to solve them. He also has no regard for the consumption of other members of the society or for their feelings about his actions. Huge empirical and experimental evidence shows that departure from these qualities is robust and significant. The failure of the existing models to incorporate bounded rationality and social concerns has proven critical in socially relevant and complex situations such as lifetime consumption and saving, taxation and expenditure policy, labour search and wage determination. The objective of this project is to bring these phenomena into the framework of neoclassical economics, to test their implications, and to tackle important applications. A novel and central feature of our approach is the attempt to retain the parsimonious methodological approach of economic modelling, which has scored groundbreaking successes in matters such as the design of auctions, markets, contracts, and voting mechanisms. Our project envisions the development of theory on individual decision making, the use of experiments to illuminate and test the theory, and the concrete application of theory - mainly to financial markets. The project will push the frontiers of the understanding of the above mentioned socially relevant situations. The explanatory power of our approach will be guaranteed by the continuous feed-back between theory and evidence- experimental and neuroexperimental, and by a departure from ad hoc modelling.
Summary
In the field of economics, individual decision making is the basic building block for studying complex environments such as markets, political systems, and social dynamics. Individual decision making is embodied in the neoclassical economically rational agent, whose only concern is the maximization of utility from his own material consumption. Two qualities of this agent are especially important for the research we will undertake: He has perfect understanding of the problems he faces - today and in the future - and unbounded computational ability to solve them. He also has no regard for the consumption of other members of the society or for their feelings about his actions. Huge empirical and experimental evidence shows that departure from these qualities is robust and significant. The failure of the existing models to incorporate bounded rationality and social concerns has proven critical in socially relevant and complex situations such as lifetime consumption and saving, taxation and expenditure policy, labour search and wage determination. The objective of this project is to bring these phenomena into the framework of neoclassical economics, to test their implications, and to tackle important applications. A novel and central feature of our approach is the attempt to retain the parsimonious methodological approach of economic modelling, which has scored groundbreaking successes in matters such as the design of auctions, markets, contracts, and voting mechanisms. Our project envisions the development of theory on individual decision making, the use of experiments to illuminate and test the theory, and the concrete application of theory - mainly to financial markets. The project will push the frontiers of the understanding of the above mentioned socially relevant situations. The explanatory power of our approach will be guaranteed by the continuous feed-back between theory and evidence- experimental and neuroexperimental, and by a departure from ad hoc modelling.
Max ERC Funding
1 399 800 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym BSMOXFORD
Project Physics Beyond the Standard Model at the LHC and with Atom Interferometers
Researcher (PI) Savas Dimopoulos
Host Institution (HI) EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH
Call Details Advanced Grant (AdG), PE2, ERC-2008-AdG
Summary Elementary particle physics is entering a spectacular new era in which experiments at the Large Hadron Collider (LHC) at CERN will soon start probing some of the deepest questions in physics, such as: Why is gravity so weak? Do elementary particles have substructure? What is the origin of mass? Are there new dimensions? Can we produce black holes in the lab? Could there be other universes with different physical laws? While the LHC pushes the energy frontier, the unprecedented precision of Atom Interferometry, has pointed me to a new tool for fundamental physics. These experiments based on the quantum interference of atoms can test General Relativity on the surface of the Earth, detect gravity waves, and test short-distance gravity, charge quantization, and quantum mechanics with unprecedented precision in the next decade. This ERC Advanced grant proposal is aimed at setting up a world-leading European center for development of a deeper theory of fundamental physics. The next 10 years is the optimal time for such studies to benefit from the wealth of new data that will emerge from the LHC, astrophysical observations and atom interferometry. This is a once-in-a-generation opportunity for making ground-breaking progress, and will open up many new research horizons.
Summary
Elementary particle physics is entering a spectacular new era in which experiments at the Large Hadron Collider (LHC) at CERN will soon start probing some of the deepest questions in physics, such as: Why is gravity so weak? Do elementary particles have substructure? What is the origin of mass? Are there new dimensions? Can we produce black holes in the lab? Could there be other universes with different physical laws? While the LHC pushes the energy frontier, the unprecedented precision of Atom Interferometry, has pointed me to a new tool for fundamental physics. These experiments based on the quantum interference of atoms can test General Relativity on the surface of the Earth, detect gravity waves, and test short-distance gravity, charge quantization, and quantum mechanics with unprecedented precision in the next decade. This ERC Advanced grant proposal is aimed at setting up a world-leading European center for development of a deeper theory of fundamental physics. The next 10 years is the optimal time for such studies to benefit from the wealth of new data that will emerge from the LHC, astrophysical observations and atom interferometry. This is a once-in-a-generation opportunity for making ground-breaking progress, and will open up many new research horizons.
Max ERC Funding
2 200 000 €
Duration
Start date: 2009-05-01, End date: 2014-04-30
Project acronym C8
Project Consistent computation of the chemistry-cloud continuum and climate change in Cyprus
Researcher (PI) Johannes Lelieveld
Host Institution (HI) THE CYPRUS RESEARCH AND EDUCATIONAL FOUNDATION
Call Details Advanced Grant (AdG), PE10, ERC-2008-AdG
Summary We have developed a new numerical method to consistently compute atmospheric trace gas and aerosol chemistry and cloud processes. The method is computationally efficient so that it can be used in climate models. For the first time cloud droplet formation on multi-component particles can be represented based on first principles rather than parameterisations. This allows for a direct coupling in models between aerosol chemical composition and the continuum between hazes and clouds as a function of ambient relative humidity. We will apply the method in a new nested global-limited area model system to study atmospheric chemistry climate interactions and anthropogenic influences. We will focus on the Mediterranean region because it is a hot spot in climate change exposed to drying and air pollution. The limited area model will also be applied as cloud-resolving model to study aerosol influences on precipitation and storm development. By simulating realistic meteorological conditions at high spatial resolution our method can be straightforwardly tested against observations. Central questions are: - How does the simulated haze-cloud continuum compare with remote sensing measurements and what is the consequence of abandoning the traditional and artificial distinction between aerosols and clouds? - How are cloud and precipitation formation influenced by atmospheric chemical composition changes? - To what extent do haze and cloud formation in polluted air exert forcings of synoptic meteorological conditions and climate? - Can aerosol pollution in the Mediterranean region exacerbate the predicted and observed drying in a changing climate? The model system is user-friendly and will facilitate air quality and climate studies by regional scientists. The project will be part of the Energy, Environment and Water Centre of the newly founded Cyprus Institute, provide input to climate impact assessments and contribute to a regional outreach programme.
Summary
We have developed a new numerical method to consistently compute atmospheric trace gas and aerosol chemistry and cloud processes. The method is computationally efficient so that it can be used in climate models. For the first time cloud droplet formation on multi-component particles can be represented based on first principles rather than parameterisations. This allows for a direct coupling in models between aerosol chemical composition and the continuum between hazes and clouds as a function of ambient relative humidity. We will apply the method in a new nested global-limited area model system to study atmospheric chemistry climate interactions and anthropogenic influences. We will focus on the Mediterranean region because it is a hot spot in climate change exposed to drying and air pollution. The limited area model will also be applied as cloud-resolving model to study aerosol influences on precipitation and storm development. By simulating realistic meteorological conditions at high spatial resolution our method can be straightforwardly tested against observations. Central questions are: - How does the simulated haze-cloud continuum compare with remote sensing measurements and what is the consequence of abandoning the traditional and artificial distinction between aerosols and clouds? - How are cloud and precipitation formation influenced by atmospheric chemical composition changes? - To what extent do haze and cloud formation in polluted air exert forcings of synoptic meteorological conditions and climate? - Can aerosol pollution in the Mediterranean region exacerbate the predicted and observed drying in a changing climate? The model system is user-friendly and will facilitate air quality and climate studies by regional scientists. The project will be part of the Energy, Environment and Water Centre of the newly founded Cyprus Institute, provide input to climate impact assessments and contribute to a regional outreach programme.
Max ERC Funding
2 196 000 €
Duration
Start date: 2009-01-01, End date: 2014-12-31
Project acronym CADRE
Project Cardiac Death and Regeneration
Researcher (PI) Michael David Schneider
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Cardiac muscle death, unmatched by muscle cell creation, is the hallmark of acute myocardial infarction and chronic cardiomyopathies. The notion of heart failure as a muscle-cell deficiency disease has driven interest worldwide in ways to increase heart muscle cell number, by over-riding cell cycle constraints, suppressing cell death, or, most directly, cell grafting. Using stem cell antigen-1, we previously identified telomerase-expressing cells in adult mouse myocardium, which have salutary properties for bona fide cardiac regeneration. Here, we seek to address systematically the mechanisms for long-term self-renewal in Sca-1+ adult cardiac progenitor cells and in the smaller side population fraction, which is clonogenic and expresses telomerase at even higher levels. Specifically, we propose to study the roles of telomerase and of the telomere-capping protein, TRF2. Aim 1, Determine the properties of adult cardiac progenitor cells in mice that lack the RNA component of telomerase (TERC). Aim 2, Determine the properties of adult cardiac progenitor cells in mice that lack the catalytic component (TERT). To distinguish between effects of these two gene products themselves versus those that depend on cumulative telomere dysfunction, G2- and G5-null mice will be compared. Aim 3, Determine the properties of adult cardiac muscle and adult cardiac progenitor cells that lack the telomere-capping protein TRF2. Aim 4, Test the prediction that forced expression of TERT and TRF2 can augment cardiac muscle engraftment in vivo and enhance the clonal derivation of adult cardiac progenitor cells in vitro, without adversely affecting the cells differentiation potential. Work proposed in Aims 1-3 would provide indispensable fundamental information about the function of endogenous telomerase in adult cardiac progenitor cells. Conversely, work in Aim 4 would test potential therapeutic implications of telomerase and a telomere-capping protein with this auspicious population.
Summary
Cardiac muscle death, unmatched by muscle cell creation, is the hallmark of acute myocardial infarction and chronic cardiomyopathies. The notion of heart failure as a muscle-cell deficiency disease has driven interest worldwide in ways to increase heart muscle cell number, by over-riding cell cycle constraints, suppressing cell death, or, most directly, cell grafting. Using stem cell antigen-1, we previously identified telomerase-expressing cells in adult mouse myocardium, which have salutary properties for bona fide cardiac regeneration. Here, we seek to address systematically the mechanisms for long-term self-renewal in Sca-1+ adult cardiac progenitor cells and in the smaller side population fraction, which is clonogenic and expresses telomerase at even higher levels. Specifically, we propose to study the roles of telomerase and of the telomere-capping protein, TRF2. Aim 1, Determine the properties of adult cardiac progenitor cells in mice that lack the RNA component of telomerase (TERC). Aim 2, Determine the properties of adult cardiac progenitor cells in mice that lack the catalytic component (TERT). To distinguish between effects of these two gene products themselves versus those that depend on cumulative telomere dysfunction, G2- and G5-null mice will be compared. Aim 3, Determine the properties of adult cardiac muscle and adult cardiac progenitor cells that lack the telomere-capping protein TRF2. Aim 4, Test the prediction that forced expression of TERT and TRF2 can augment cardiac muscle engraftment in vivo and enhance the clonal derivation of adult cardiac progenitor cells in vitro, without adversely affecting the cells differentiation potential. Work proposed in Aims 1-3 would provide indispensable fundamental information about the function of endogenous telomerase in adult cardiac progenitor cells. Conversely, work in Aim 4 would test potential therapeutic implications of telomerase and a telomere-capping protein with this auspicious population.
Max ERC Funding
2 497 576 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym CANCER&AGEING
Project COMMOM MECHANISMS UNDERLYING CANCER AND AGEING
Researcher (PI) Manuel Serrano
Host Institution (HI) FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Call Details Advanced Grant (AdG), LS1, ERC-2008-AdG
Summary "In recent years, we have made significant contributions to the understanding of the tumour suppressors p53, p16INK4a, and ARF, particularly in relation with cellular senescence and aging. The current project is motivated by two hypothesis: 1) that the INK4/ARF locus is a sensor of epigenetic damage and this is at the basis of its activation by oncogenes and aging; and, 2) that the accumulation of cellular damage and stress is at the basis of both cancer and aging, and consequently ""anti-damage genes"", such as tumour suppressors, simultaneously counteract both cancer and aging. With regard to the INK4/ARF locus, the project includes: 1.1) the generation of null mice for the Regulatory Domain (RD) thought to be essential for the proper regulation of the locus; 1.2) the study of the INK4/ARF anti-sense transcription and its importance for the assembly of Polycomb repressive complexes; 1.3) the generation of mice carrying the human INK4/ARF locus to analyze, among other aspects, whether the known differences between the human and murine loci are ""locus autonomous""; and, 1.4) to analyze the INK4/ARF locus in the process of epigenetic reprogramming both from ES cells to differentiated cells and, conversely, from differentiated cells to induced-pluripotent stem (iPS) cells. With regard to the impact of ""anti-damage genes"" on cancer and aging, the project includes: 2.1) the analysis of the aging of super-INK4/ARF mice and super-p53 mice; 2.2) we have generated super-PTEN mice and we will examine whether PTEN not only confers cancer resistance but also anti-aging activity; and, finally, 2.3) we have generated super-SIRT1 mice, which is among the best-characterized anti-aging genes in non-mammalian model systems (where it is named Sir2) involved in protection from metabolic damage, and we will study the cancer and aging of these mice. Together, this project will significantly advance our understanding of the molecular mechanisms underlying cancer and aging."
Summary
"In recent years, we have made significant contributions to the understanding of the tumour suppressors p53, p16INK4a, and ARF, particularly in relation with cellular senescence and aging. The current project is motivated by two hypothesis: 1) that the INK4/ARF locus is a sensor of epigenetic damage and this is at the basis of its activation by oncogenes and aging; and, 2) that the accumulation of cellular damage and stress is at the basis of both cancer and aging, and consequently ""anti-damage genes"", such as tumour suppressors, simultaneously counteract both cancer and aging. With regard to the INK4/ARF locus, the project includes: 1.1) the generation of null mice for the Regulatory Domain (RD) thought to be essential for the proper regulation of the locus; 1.2) the study of the INK4/ARF anti-sense transcription and its importance for the assembly of Polycomb repressive complexes; 1.3) the generation of mice carrying the human INK4/ARF locus to analyze, among other aspects, whether the known differences between the human and murine loci are ""locus autonomous""; and, 1.4) to analyze the INK4/ARF locus in the process of epigenetic reprogramming both from ES cells to differentiated cells and, conversely, from differentiated cells to induced-pluripotent stem (iPS) cells. With regard to the impact of ""anti-damage genes"" on cancer and aging, the project includes: 2.1) the analysis of the aging of super-INK4/ARF mice and super-p53 mice; 2.2) we have generated super-PTEN mice and we will examine whether PTEN not only confers cancer resistance but also anti-aging activity; and, finally, 2.3) we have generated super-SIRT1 mice, which is among the best-characterized anti-aging genes in non-mammalian model systems (where it is named Sir2) involved in protection from metabolic damage, and we will study the cancer and aging of these mice. Together, this project will significantly advance our understanding of the molecular mechanisms underlying cancer and aging."
Max ERC Funding
2 000 000 €
Duration
Start date: 2009-04-01, End date: 2015-03-31
