Project acronym BODY-OWNERSHIP
Project Neural mechanisms of body ownership and the projection of ownership onto artificial bodies
Researcher (PI) H. Henrik Ehrsson
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS4, ERC-2007-StG
Summary How do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.
Summary
How do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.
Max ERC Funding
909 850 €
Duration
Start date: 2008-12-01, End date: 2013-11-30
Project acronym CAAXPROCESSINGHUMDIS
Project CAAX Protein Processing in Human DIsease: From Cancer to Progeria
Researcher (PI) Martin Olof Bergö
Host Institution (HI) GOETEBORGS UNIVERSITET
Call Details Starting Grant (StG), LS6, ERC-2007-StG
Summary My objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.
Summary
My objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.
Max ERC Funding
1 689 600 €
Duration
Start date: 2008-06-01, End date: 2013-05-31
Project acronym DII
Project The Design of International Institutions: Legitimacy, Effectiveness and Distribution in Global Governance
Researcher (PI) Jonas Tallberg
Host Institution (HI) STOCKHOLMS UNIVERSITET
Call Details Starting Grant (StG), SH2, ERC-2007-StG
Summary One of the most profound trends in global governance over the past two decades is the growing extent to which international institutions offer mechanisms for the participation of transnational actors. This project will explore two central research questions, pertaining to the causes and effects of this shift in the design of international institutions: (1) Why have international institutions increasingly opened up to transnational actor involvement? (2) What are the consequences of involving transnational actors for the democratic legitimacy, problem-solving effectiveness, and distributional effects of international institutions? These are research questions that previously have not been explored systematically in existing literatures on international institutional design, transnational actors in global governance, and democracy beyond the nation-state. This project opens up a new research agenda on the design of international institutions through an ambitious combination of novel theory development and comparative empirical research. Theoretically, the project develops and tests alternative hypotheses about the causes and effects of transnational participation in international policy-making. Empirically, the project explores the dynamics of transnational participation through comparative case studies of five major international institutions, supplemented with a large-n mapping of formal mechanisms of transnational access in a broader sample of institutions. The project will help to establish an internationally competitive research group of post-doc researchers and Ph.D. students devoted to international institutional design, and consolidate the position of the principal investigator as a leading researcher in this field.
Summary
One of the most profound trends in global governance over the past two decades is the growing extent to which international institutions offer mechanisms for the participation of transnational actors. This project will explore two central research questions, pertaining to the causes and effects of this shift in the design of international institutions: (1) Why have international institutions increasingly opened up to transnational actor involvement? (2) What are the consequences of involving transnational actors for the democratic legitimacy, problem-solving effectiveness, and distributional effects of international institutions? These are research questions that previously have not been explored systematically in existing literatures on international institutional design, transnational actors in global governance, and democracy beyond the nation-state. This project opens up a new research agenda on the design of international institutions through an ambitious combination of novel theory development and comparative empirical research. Theoretically, the project develops and tests alternative hypotheses about the causes and effects of transnational participation in international policy-making. Empirically, the project explores the dynamics of transnational participation through comparative case studies of five major international institutions, supplemented with a large-n mapping of formal mechanisms of transnational access in a broader sample of institutions. The project will help to establish an internationally competitive research group of post-doc researchers and Ph.D. students devoted to international institutional design, and consolidate the position of the principal investigator as a leading researcher in this field.
Max ERC Funding
1 651 200 €
Duration
Start date: 2009-01-01, End date: 2014-12-31
Project acronym ERIKLINDAHLERC2007
Project Multiscale and Distributed Computing Algorithms for Biomolecular Simulation and Efficient Free Energy Calculations
Researcher (PI) Erik Lindahl
Host Institution (HI) KUNGLIGA TEKNISKA HOEGSKOLAN
Call Details Starting Grant (StG), PE4, ERC-2007-StG
Summary The long-term goal of our research is to advance the state-of-the-art in molecular simulation algorithms by 4-5 orders of magnitude, particularly in the context of the GROMACS software we are developing. This is an immense challenge, but with huge potential rewards: it will be an amazing virtual microscope for basic chemistry, polymer and material science research; it could help us understand the molecular basis of diseases such as Creutzfeldt-Jacob, and it would enable rational design rather than random screening for future drugs. To realize it, we will focus on four critical topics: • ALGORITHMS FOR SIMULATION ON GRAPHICS AND OTHER STREAMING PROCESSORS: Graphics cards and the test Intel 80-core chip are not only the most powerful processors available, but this type of streaming architectures will power many supercomputers in 3-5 years, and it is thus critical that we design new “streamable” MD algorithms. • MULTISCALE MODELING: We will develop virtual-site-based methods to bridge atomic and mesoscopic dynamics, QM/MM, and mixed explicit/implicit solvent models with water layers around macromolecules. • MULTI-LEVEL PARALLEL & DISTRIBUTED SIMULATION: Distributed computing provides virtually infinite computer power, but has been limited to small systems. We will address this by combining SMP parallelization and Markov State Models that partition phase space into transition/local dynamics to enable distributed simulation of arbitrary systems. • EFFICIENT FREE ENERGY CALCULATIONS: We will design algorithms for multi-conformational parallel sampling, implement Bennett Acceptance Ratios in Gromacs, correction terms for PME lattice sums, and combine standard force fields with polarization/multipoles, e.g. Amoeba. We have a very strong track record of converting methodological advances into applications, and the results will have impact on a wide range of fields from biomolecules and polymer science through material simulations and nanotechnology.
Summary
The long-term goal of our research is to advance the state-of-the-art in molecular simulation algorithms by 4-5 orders of magnitude, particularly in the context of the GROMACS software we are developing. This is an immense challenge, but with huge potential rewards: it will be an amazing virtual microscope for basic chemistry, polymer and material science research; it could help us understand the molecular basis of diseases such as Creutzfeldt-Jacob, and it would enable rational design rather than random screening for future drugs. To realize it, we will focus on four critical topics: • ALGORITHMS FOR SIMULATION ON GRAPHICS AND OTHER STREAMING PROCESSORS: Graphics cards and the test Intel 80-core chip are not only the most powerful processors available, but this type of streaming architectures will power many supercomputers in 3-5 years, and it is thus critical that we design new “streamable” MD algorithms. • MULTISCALE MODELING: We will develop virtual-site-based methods to bridge atomic and mesoscopic dynamics, QM/MM, and mixed explicit/implicit solvent models with water layers around macromolecules. • MULTI-LEVEL PARALLEL & DISTRIBUTED SIMULATION: Distributed computing provides virtually infinite computer power, but has been limited to small systems. We will address this by combining SMP parallelization and Markov State Models that partition phase space into transition/local dynamics to enable distributed simulation of arbitrary systems. • EFFICIENT FREE ENERGY CALCULATIONS: We will design algorithms for multi-conformational parallel sampling, implement Bennett Acceptance Ratios in Gromacs, correction terms for PME lattice sums, and combine standard force fields with polarization/multipoles, e.g. Amoeba. We have a very strong track record of converting methodological advances into applications, and the results will have impact on a wide range of fields from biomolecules and polymer science through material simulations and nanotechnology.
Max ERC Funding
992 413 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym GENOMIC STABILITY
Project Genomic stability -chromosome segregation and repair
Researcher (PI) Camilla Björkegren Sjögren
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary The eukaryotic genome combines a highly dynamic nature with stable transmission of genetic information from mother to daughter cells. This is achieved by a plethora of protein networks regulating processes such as chromosome duplication, segregation and repair. The principal aim of our research is to determine the molecular interplay between chromosome segregation and repair. Accurate execution of these two events is crucial for the maintenance of genome stability, which in turn is essential for life. Additionally, erroneous segregation or repair leads to chromosomal aberrations that are linked to tumor formation and human developmental syndromes. Thus, our investigations are not only crucial in a basic research perspective, but important also for the understanding of the causes of human disease. The research is based on the budding yeast model system, and combines genome-wide analysis of protein-chromosome interactions with cell-based experimental systems. Our investigations have until now revealed that chromosome segregation and repair are directly linked through two evolutionary conserved SMC (Structural Maintenance of Chromosomes) protein complexes, Cohesin and the Smc5/6 complex. The project now further explores the molecular details of this connection, bringing light into this unexplored area of research, and deciphering the cellular defense against genomic alterations connected to cancer and developmental diseases.
Summary
The eukaryotic genome combines a highly dynamic nature with stable transmission of genetic information from mother to daughter cells. This is achieved by a plethora of protein networks regulating processes such as chromosome duplication, segregation and repair. The principal aim of our research is to determine the molecular interplay between chromosome segregation and repair. Accurate execution of these two events is crucial for the maintenance of genome stability, which in turn is essential for life. Additionally, erroneous segregation or repair leads to chromosomal aberrations that are linked to tumor formation and human developmental syndromes. Thus, our investigations are not only crucial in a basic research perspective, but important also for the understanding of the causes of human disease. The research is based on the budding yeast model system, and combines genome-wide analysis of protein-chromosome interactions with cell-based experimental systems. Our investigations have until now revealed that chromosome segregation and repair are directly linked through two evolutionary conserved SMC (Structural Maintenance of Chromosomes) protein complexes, Cohesin and the Smc5/6 complex. The project now further explores the molecular details of this connection, bringing light into this unexplored area of research, and deciphering the cellular defense against genomic alterations connected to cancer and developmental diseases.
Max ERC Funding
900 000 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym GLOBALVISION
Project Global Optimization Methods in Computer Vision, Pattern Recognition and Medical Imaging
Researcher (PI) Fredrik Kahl
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), PE5, ERC-2007-StG
Summary Computer vision concerns itself with understanding the real world through the analysis of images. Typical problems are object recognition, medical image segmentation, geometric reconstruction problems and navigation of autonomous vehicles. Such problems often lead to complicated optimization problems with a mixture of discrete and continuous variables, or even infinite dimensional variables in terms of curves and surfaces. Today, state-of-the-art in solving these problems generally relies on heuristic methods that generate only local optima of various qualities. During the last few years, work by the applicant, co-workers, and others has opened new possibilities. This research project builds on this. We will in this project focus on developing new global optimization methods for computing high-quality solutions for a broad class of problems. A guiding principle will be to relax the original, complicated problem to an approximate, simpler one to which globally optimal solutions can more easily be computed. Technically, this relaxed problem often is convex. A crucial point in this approach is to estimate the quality of the exact solution of the approximate problem compared to the (unknown) global optimum of the original problem. Preliminary results have been well received by the research community and we now wish to extend this work to more difficult and more general problem settings, resulting in thorough re-examination of algorithms used widely in different and trans-disciplinary fields. This project is to be considered as a basic research project with relevance to industry. The expected outcome is new knowledge spread to a wide community through scientific papers published at international journals and conferences as well as publicly available software.
Summary
Computer vision concerns itself with understanding the real world through the analysis of images. Typical problems are object recognition, medical image segmentation, geometric reconstruction problems and navigation of autonomous vehicles. Such problems often lead to complicated optimization problems with a mixture of discrete and continuous variables, or even infinite dimensional variables in terms of curves and surfaces. Today, state-of-the-art in solving these problems generally relies on heuristic methods that generate only local optima of various qualities. During the last few years, work by the applicant, co-workers, and others has opened new possibilities. This research project builds on this. We will in this project focus on developing new global optimization methods for computing high-quality solutions for a broad class of problems. A guiding principle will be to relax the original, complicated problem to an approximate, simpler one to which globally optimal solutions can more easily be computed. Technically, this relaxed problem often is convex. A crucial point in this approach is to estimate the quality of the exact solution of the approximate problem compared to the (unknown) global optimum of the original problem. Preliminary results have been well received by the research community and we now wish to extend this work to more difficult and more general problem settings, resulting in thorough re-examination of algorithms used widely in different and trans-disciplinary fields. This project is to be considered as a basic research project with relevance to industry. The expected outcome is new knowledge spread to a wide community through scientific papers published at international journals and conferences as well as publicly available software.
Max ERC Funding
1 440 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym MEDIA AND POLICY
Project The impact of mass media on public policy
Researcher (PI) David Strömberg
Host Institution (HI) STOCKHOLMS UNIVERSITET
Call Details Starting Grant (StG), SH1, ERC-2007-StG
Summary This project will study political economics issues, that is, how public policies are influenced by political considerations. The emphasis is on the mass media's role in shaping government policies. A smaller part will also analyze how different political institutions and economic outcomes influence policy and the impact of extreme weather events. The project will mainly be empirical, using statistical methods with a focus on identifying causal effects, rather than correlations. The study of media effects will analyze the political impact of having a press actively covering politics. This is an important issue, largely unanswered because the presence of an active press is endogenous to things like corruption and voter information. We will address this question in the special case of media coverage of US Congressional elections. To identify the effect of news, we will use the fact that the amount of coverage is driven to a large extent by the coincidental match between media markets and congressional districts. We intend to analyze the effect of active press coverage on, (i) voter information, (ii) politicians actions, and (iii) federal funds per capita. The project will also investigate how political institutions and economic outcomes influences the health impacts (such as mortality among old and infants) of weather extremes. Historical weather data at a very detailed geographical level will be combined with socio-economic data in a panel (longitudinal) form. This is joint work with meteorologists who will construct historical weather data at fine grids across the globe. The part dealing with structural political economics aims to develop a framework for investigating the effects of institutions on economic policy. In existing work, there is a disconnect between the theoretical modelling and empirical applications. The aim is to close this gap.
Summary
This project will study political economics issues, that is, how public policies are influenced by political considerations. The emphasis is on the mass media's role in shaping government policies. A smaller part will also analyze how different political institutions and economic outcomes influence policy and the impact of extreme weather events. The project will mainly be empirical, using statistical methods with a focus on identifying causal effects, rather than correlations. The study of media effects will analyze the political impact of having a press actively covering politics. This is an important issue, largely unanswered because the presence of an active press is endogenous to things like corruption and voter information. We will address this question in the special case of media coverage of US Congressional elections. To identify the effect of news, we will use the fact that the amount of coverage is driven to a large extent by the coincidental match between media markets and congressional districts. We intend to analyze the effect of active press coverage on, (i) voter information, (ii) politicians actions, and (iii) federal funds per capita. The project will also investigate how political institutions and economic outcomes influences the health impacts (such as mortality among old and infants) of weather extremes. Historical weather data at a very detailed geographical level will be combined with socio-economic data in a panel (longitudinal) form. This is joint work with meteorologists who will construct historical weather data at fine grids across the globe. The part dealing with structural political economics aims to develop a framework for investigating the effects of institutions on economic policy. In existing work, there is a disconnect between the theoretical modelling and empirical applications. The aim is to close this gap.
Max ERC Funding
799 945 €
Duration
Start date: 2008-09-01, End date: 2014-08-31
Project acronym MINATRAN
Project Probing the Micro-Nano Transition: Theoretical and Experimental Foundations, Simulations and Applications
Researcher (PI) Aikaterini Aifanti
Host Institution (HI) ARISTOTELIO PANEPISTIMIO THESSALONIKIS - EIDIKOS LOGARIASMOS KONDILION EREVNAS
Call Details Starting Grant (StG), PE6, ERC-2007-StG
Summary The objective is to develop a robust multifunctional framework/probe for capturing the evolution of deformation and failure in a variety of processes at the micro-nano transition regime. An interdisciplinary approach will be pursued based on fundamental theory and experiment, in conjunction with multiscale simulations for micro/nanotechnology applications. The approach is unconventional as it ventures to extend continuum mechanics down to the micro/nano regime and verify this through nanoindentation and atomic force microscopy techniques. It is also unique as the new phenomenology introduced for establishing this extension (higher order gradients accounting for microscopic processes and interfacial energy terms accounting for nanoscopic phenomena) will be substantiated through hybrid (ab initio-atomistic-defect-finite element) simulations. The framework will be employed to consider fracture and size effects in a number of micro-nano scale transition configurations ranging from nanograined aggregates and nanolayered structures to nanotubes and micropillars, and from Li-ion battery electrodes to bioactive interfaces. Other micro/nano objects such as quantum dots, nanowires and NEMS/MEMS devices, as well as biomolecular microcrystalline membranes leading to living cell division will be considered. In a sense this “scale” transition theory is reminiscent in scope to Landau’s “phase” transition theory where a variety of different physical phenomena can be treated within a common framework. This optimism stems from the PI’s previous success with this approach, as well as Smalley’s remark that the “laws of continuum mechanics are amazingly robust for treating even intrinsically discrete objects only a few atoms in diameter”. A good mix of young researchers and mature scholars will be employed, thus connecting people and ideas through joint publications and scholarly activities in a critical area of fundamental and applied research.
Summary
The objective is to develop a robust multifunctional framework/probe for capturing the evolution of deformation and failure in a variety of processes at the micro-nano transition regime. An interdisciplinary approach will be pursued based on fundamental theory and experiment, in conjunction with multiscale simulations for micro/nanotechnology applications. The approach is unconventional as it ventures to extend continuum mechanics down to the micro/nano regime and verify this through nanoindentation and atomic force microscopy techniques. It is also unique as the new phenomenology introduced for establishing this extension (higher order gradients accounting for microscopic processes and interfacial energy terms accounting for nanoscopic phenomena) will be substantiated through hybrid (ab initio-atomistic-defect-finite element) simulations. The framework will be employed to consider fracture and size effects in a number of micro-nano scale transition configurations ranging from nanograined aggregates and nanolayered structures to nanotubes and micropillars, and from Li-ion battery electrodes to bioactive interfaces. Other micro/nano objects such as quantum dots, nanowires and NEMS/MEMS devices, as well as biomolecular microcrystalline membranes leading to living cell division will be considered. In a sense this “scale” transition theory is reminiscent in scope to Landau’s “phase” transition theory where a variety of different physical phenomena can be treated within a common framework. This optimism stems from the PI’s previous success with this approach, as well as Smalley’s remark that the “laws of continuum mechanics are amazingly robust for treating even intrinsically discrete objects only a few atoms in diameter”. A good mix of young researchers and mature scholars will be employed, thus connecting people and ideas through joint publications and scholarly activities in a critical area of fundamental and applied research.
Max ERC Funding
1 128 400 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym PAGE
Project The role of mRNA-processing bodies in ageing
Researcher (PI) Popi Syntichaki
Host Institution (HI) IDRYMA IATROVIOLOGIKON EREUNON AKADEMIAS ATHINON
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary Recently, we and others have revealed that, in the nematode Caenorhabditis elegans, reduction of protein synthesis rates in somatic cells extends lifespan. Based on this, we postulate that the molecular factors and mechanisms that control the mRNA metabolism in post-mitotic cells are critical determinants of ageing. This project will validate this hypothesis using C. elegans as main model system, but parallel studies in Saccharomyces cerevisiae and Drosophila melanogaster will prove the conservation of our observations. The cellular factors involved in mRNA metabolism (degradation/storage) are localized at specific particles in the cytoplasm of all eukaryotic cells, termed mRNA processing (P) bodies. Additionally, stress granules are cytoplasmic sites of mRNA-metabolism that are formed under stress conditions in mammalian cells. The objectives of this project include: -Monitoring of both P bodies and stress granules in adult worms and characterization of the age-related alterations in their profile, by immunostaining and real-time fluorescence imaging -Direct alterations in the expression of genes encoding factors of each particle in wild-type worms and analysis of the effects on lifespan and stress resistance -Comparison of the age-related changes in the profile of P bodies and stress granules between wild-type and long- or short-lived mutant worms -Direct alterations in the expression of genes encoding factors of each particle in worms with altered lifespan and investigation of the effects on lifespan and stress resistance -Observation of the age-related alterations in the profile of P bodies in yeast and flies, both in wild-type and long-lived strains. The rationale for this project is to provide insight into the modulation of ageing and stress resistance at the level of mRNA metabolism, which is a yet unexplored field of the biology of ageing and global stress response.
Summary
Recently, we and others have revealed that, in the nematode Caenorhabditis elegans, reduction of protein synthesis rates in somatic cells extends lifespan. Based on this, we postulate that the molecular factors and mechanisms that control the mRNA metabolism in post-mitotic cells are critical determinants of ageing. This project will validate this hypothesis using C. elegans as main model system, but parallel studies in Saccharomyces cerevisiae and Drosophila melanogaster will prove the conservation of our observations. The cellular factors involved in mRNA metabolism (degradation/storage) are localized at specific particles in the cytoplasm of all eukaryotic cells, termed mRNA processing (P) bodies. Additionally, stress granules are cytoplasmic sites of mRNA-metabolism that are formed under stress conditions in mammalian cells. The objectives of this project include: -Monitoring of both P bodies and stress granules in adult worms and characterization of the age-related alterations in their profile, by immunostaining and real-time fluorescence imaging -Direct alterations in the expression of genes encoding factors of each particle in wild-type worms and analysis of the effects on lifespan and stress resistance -Comparison of the age-related changes in the profile of P bodies and stress granules between wild-type and long- or short-lived mutant worms -Direct alterations in the expression of genes encoding factors of each particle in worms with altered lifespan and investigation of the effects on lifespan and stress resistance -Observation of the age-related alterations in the profile of P bodies in yeast and flies, both in wild-type and long-lived strains. The rationale for this project is to provide insight into the modulation of ageing and stress resistance at the level of mRNA metabolism, which is a yet unexplored field of the biology of ageing and global stress response.
Max ERC Funding
1 080 000 €
Duration
Start date: 2008-09-01, End date: 2014-08-31
Project acronym PHOTOCHROMES
Project Photochromic Systems for Solid State Molecular Electronic Devices and Light-Activated Cancer Drugs
Researcher (PI) Joakim Andréasson
Host Institution (HI) CHALMERS TEKNISKA HOEGSKOLA AB
Call Details Starting Grant (StG), PE4, ERC-2007-StG
Summary Photochromic molecules, or photochromes, can be reversibly isomerized between two thermally stable forms by exposure to light of different wavelengths. Upon isomerization, properties such as excitation energies, redox properties, charge distribution, and structure experience significant changes. These changes can be harnessed to switch “on” or “off” the action of a variety of photophysical processes in the photochromic constructs, e.g., energy and electron transfer. Until now, the focus of my research has been to show proof of principle for a large selection of molecule-based photonically controlled logic devices (solution based) with the functional basis in the switching of the transfer processes mentioned above. Now, I wish to extend the study to include experiments in the solid state, e.g., polymer matrices. Taking the step into doing solid state chemistry is not only a prerequisite for any real-world application. It will also allow for experiments that cannot be performed in fluid solution, such as aligning molecules in a stretched film for chemistry with polarized light, and immobilization of molecules for selective addressing in a three-dimensional array of volume elements. Furthermore, I intend to investigate the possibility to photonically control the membrane penetrating and the DNA-binding abilities of photochromes, aiming at, in a long-term perspective, light-activated cancer drugs. Due to the fact that both the structure and the charge distribution of a photochrome may change drastically upon isomerization, one of the two isomeric forms is often suitable for penetrating a membrane. Inside the membrane, e.g., in a cell, the photochrome can be photo-isomerized to a structure with high affinity for strong binding to DNA. Upon binding, transcription is inhibited and the cell dies. If desired, pH-sensitivity and two-photon processes could be used to further increase the selectivity in addressing very specific regions of the body, such as a tumor.
Summary
Photochromic molecules, or photochromes, can be reversibly isomerized between two thermally stable forms by exposure to light of different wavelengths. Upon isomerization, properties such as excitation energies, redox properties, charge distribution, and structure experience significant changes. These changes can be harnessed to switch “on” or “off” the action of a variety of photophysical processes in the photochromic constructs, e.g., energy and electron transfer. Until now, the focus of my research has been to show proof of principle for a large selection of molecule-based photonically controlled logic devices (solution based) with the functional basis in the switching of the transfer processes mentioned above. Now, I wish to extend the study to include experiments in the solid state, e.g., polymer matrices. Taking the step into doing solid state chemistry is not only a prerequisite for any real-world application. It will also allow for experiments that cannot be performed in fluid solution, such as aligning molecules in a stretched film for chemistry with polarized light, and immobilization of molecules for selective addressing in a three-dimensional array of volume elements. Furthermore, I intend to investigate the possibility to photonically control the membrane penetrating and the DNA-binding abilities of photochromes, aiming at, in a long-term perspective, light-activated cancer drugs. Due to the fact that both the structure and the charge distribution of a photochrome may change drastically upon isomerization, one of the two isomeric forms is often suitable for penetrating a membrane. Inside the membrane, e.g., in a cell, the photochrome can be photo-isomerized to a structure with high affinity for strong binding to DNA. Upon binding, transcription is inhibited and the cell dies. If desired, pH-sensitivity and two-photon processes could be used to further increase the selectivity in addressing very specific regions of the body, such as a tumor.
Max ERC Funding
1 000 000 €
Duration
Start date: 2008-09-01, End date: 2013-08-31