Project acronym CDNF
Project Compartmentalization and dynamics of Nuclear functions
Researcher (PI) Angela Taddei
Host Institution (HI) INSTITUT CURIE
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary The eukaryotic genome is packaged into large-scale chromatin structures that occupy distinct domains in the nucleus and this organization is now seen as a key contributor to genome functions. Two key functions of the genome can take advantage of nuclear organization: regulated gene expression and the propagation of a stable genome. To understand these fundamental processes, we have chosen to use yeast as a model system that allows genetics, molecular biology and advanced live microscopy approaches to be combined. Budding yeast have been very powerful to demonstrate that gene position can play an active role in regulating gene expression. Distinct subcompartments dedicated to either gene silencing or activation of specific genes are positioned at the nuclear periphery. To gain insight into the mechanisms underlying this sub-compartmentalization, we will address three complementary issues: - What are the mechanisms involved in the establishment and maintenance of silent nuclear compartments? - How and why are some activated genes recruited to the nuclear periphery? - What are the relationships between repressive and activating nuclear compartments? Concerning the maintenance of genome integrity, recent advances in yeast highlight the importance of nuclear architecture. However, how nuclear organization influences the formation and processing of DNA lesions remain poorly understood. We will focus on two main questions: - How and where in the nucleus are double strand breaks recognized, processed, and repaired? - Where do breaks or gaps resulting from replicative stress at 'fragile sites' arise in the nucleus and how does nuclear organization influence their stability? We hope to gain a better understanding of the mechanisms presiding nuclear organization and its importance for genome functions. These mechanisms are likely to be conserved and will be subsequently tested in higher eukaryotic cells.
Summary
The eukaryotic genome is packaged into large-scale chromatin structures that occupy distinct domains in the nucleus and this organization is now seen as a key contributor to genome functions. Two key functions of the genome can take advantage of nuclear organization: regulated gene expression and the propagation of a stable genome. To understand these fundamental processes, we have chosen to use yeast as a model system that allows genetics, molecular biology and advanced live microscopy approaches to be combined. Budding yeast have been very powerful to demonstrate that gene position can play an active role in regulating gene expression. Distinct subcompartments dedicated to either gene silencing or activation of specific genes are positioned at the nuclear periphery. To gain insight into the mechanisms underlying this sub-compartmentalization, we will address three complementary issues: - What are the mechanisms involved in the establishment and maintenance of silent nuclear compartments? - How and why are some activated genes recruited to the nuclear periphery? - What are the relationships between repressive and activating nuclear compartments? Concerning the maintenance of genome integrity, recent advances in yeast highlight the importance of nuclear architecture. However, how nuclear organization influences the formation and processing of DNA lesions remain poorly understood. We will focus on two main questions: - How and where in the nucleus are double strand breaks recognized, processed, and repaired? - Where do breaks or gaps resulting from replicative stress at 'fragile sites' arise in the nucleus and how does nuclear organization influence their stability? We hope to gain a better understanding of the mechanisms presiding nuclear organization and its importance for genome functions. These mechanisms are likely to be conserved and will be subsequently tested in higher eukaryotic cells.
Max ERC Funding
1 000 000 €
Duration
Start date: 2008-09-01, End date: 2014-05-31
Project acronym CEPODRO
Project Cell polarization in Drosophila
Researcher (PI) Yohanns Bellaiche
Host Institution (HI) INSTITUT CURIE
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Cell polarity is fundamental to many aspects of cell and developmental biology and it is implicated in differentiation, proliferation and morphogenesis in both unicellular and multi-cellular organisms. We study the mechanisms that regulate cell polarity during both asymmetric cell division and epithelial cell polarization in Drosophila. To understand these fundamental processes, we are currently using two complementary approaches. Firstly, we are coupling genetic tools to state of the art time-lapse microscopy to genetically dissect the mechanisms of cortical cell polarization and mitotic spindle orientation. Secondly, we are introducing two innovative inter-disciplinary methodologies into the fields of cell and developmental biology: 1) single molecule imaging during asymmetric cell division, to unravel the mechanism of polarized protein distribution within the cell; 2) multi-scale tensor analysis of epithelial tissues to describe and understand how epithelial tissues grow, acquire and maintain their shape and organization during development. Using both conventional and innovative methodologies, our goals over the next four years are to better understand how molecules and protein complexes move and are activated at different locations within the cell and how cell polarization impacts on cell identities and on epithelial tissue growth and morphogenesis. Since the mechanisms underlying cell polarization are conserved throughout evolution, the proposed experiments will improve our understanding of these processes not only in Drosophila, but in all animals.
Summary
Cell polarity is fundamental to many aspects of cell and developmental biology and it is implicated in differentiation, proliferation and morphogenesis in both unicellular and multi-cellular organisms. We study the mechanisms that regulate cell polarity during both asymmetric cell division and epithelial cell polarization in Drosophila. To understand these fundamental processes, we are currently using two complementary approaches. Firstly, we are coupling genetic tools to state of the art time-lapse microscopy to genetically dissect the mechanisms of cortical cell polarization and mitotic spindle orientation. Secondly, we are introducing two innovative inter-disciplinary methodologies into the fields of cell and developmental biology: 1) single molecule imaging during asymmetric cell division, to unravel the mechanism of polarized protein distribution within the cell; 2) multi-scale tensor analysis of epithelial tissues to describe and understand how epithelial tissues grow, acquire and maintain their shape and organization during development. Using both conventional and innovative methodologies, our goals over the next four years are to better understand how molecules and protein complexes move and are activated at different locations within the cell and how cell polarization impacts on cell identities and on epithelial tissue growth and morphogenesis. Since the mechanisms underlying cell polarization are conserved throughout evolution, the proposed experiments will improve our understanding of these processes not only in Drosophila, but in all animals.
Max ERC Funding
1 159 000 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym CORTEXSELFCONTROL
Project Self-Modulating Neurons in the Cerebral Cortex: From Molecular Mechanisms to Cortical Network Activities
Researcher (PI) Alberto Bacci
Host Institution (HI) INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE
Call Details Starting Grant (StG), LS4, ERC-2007-StG
Summary In the mammalian brain, the neocortex is the site where sensory information is integrated into complex cognitive functions. This is accomplished by the activity of both principal glutamatergic neurons and locally-projecting inhibitory GABAergic interneurons, interconnected in complex networks. Inhibitory neurons play several key roles in neocortical function. For example, they shape sensory receptive fields and drive several high frequency network oscillations. On the other hand, defects in their function can lead to devastating diseases, such as epilepsy and schizophrenia. Cortical interneurons represent a highly heterogeneous cell population. Understanding the specific role of each interneuron subtype within cortical microcircuits is still a crucial open question. We have examined properties of two major functional interneuron subclasses in neocortical layer V: fast-spiking (FS) and low-threshold spiking (LTS) cells. Our previous data indicate that each group expresses a novel form of self inhibition, namely autaptic inhibitory transmission in FS cells and an endocannabinoid-mediated slow self inhibition in LTS interneurons. In this proposal we will address three major questions relevant to self-inhibition of neocortical interneurons: 1) What is the role of FS cell autapses in coordinating fast network synchrony? 2) What are the molecular mechanisms underlying autaptic asynchronous release, prolonging FS cell self-inhibition by several seconds, and what is its relevance during physiological and pathological network activities? 3) What are the induction mechanisms, the molecular players involved and the functional roles within cortical microcircuits of the endocannabinoid-mediated long-lasting self-inhibition in LTS interneurons? Results of these experiments will lead to a better understanding of GABAergic interneuron regulation of neocortical excitability, relevant to both normal and pathological cortical function.
Summary
In the mammalian brain, the neocortex is the site where sensory information is integrated into complex cognitive functions. This is accomplished by the activity of both principal glutamatergic neurons and locally-projecting inhibitory GABAergic interneurons, interconnected in complex networks. Inhibitory neurons play several key roles in neocortical function. For example, they shape sensory receptive fields and drive several high frequency network oscillations. On the other hand, defects in their function can lead to devastating diseases, such as epilepsy and schizophrenia. Cortical interneurons represent a highly heterogeneous cell population. Understanding the specific role of each interneuron subtype within cortical microcircuits is still a crucial open question. We have examined properties of two major functional interneuron subclasses in neocortical layer V: fast-spiking (FS) and low-threshold spiking (LTS) cells. Our previous data indicate that each group expresses a novel form of self inhibition, namely autaptic inhibitory transmission in FS cells and an endocannabinoid-mediated slow self inhibition in LTS interneurons. In this proposal we will address three major questions relevant to self-inhibition of neocortical interneurons: 1) What is the role of FS cell autapses in coordinating fast network synchrony? 2) What are the molecular mechanisms underlying autaptic asynchronous release, prolonging FS cell self-inhibition by several seconds, and what is its relevance during physiological and pathological network activities? 3) What are the induction mechanisms, the molecular players involved and the functional roles within cortical microcircuits of the endocannabinoid-mediated long-lasting self-inhibition in LTS interneurons? Results of these experiments will lead to a better understanding of GABAergic interneuron regulation of neocortical excitability, relevant to both normal and pathological cortical function.
Max ERC Funding
996 000 €
Duration
Start date: 2008-10-01, End date: 2014-03-31
Project acronym E3ARTHS
Project Exoplanets and Early Earth Atmospheric Research: THeories and Simulations
Researcher (PI) Franck Selsis
Host Institution (HI) UNIVERSITE DE BORDEAUX
Call Details Starting Grant (StG), PE7, ERC-2007-StG
Summary This program is dedicated to the simulation and characterization of Extrasolar Terrestrial Planet (ETP) atmospheres. Thanks to new generation codes, the team E3ARTHS aims to provide a top expertise in a key domain of astrobiology: the origin, evolution and identification of habitable worlds, and the quest for biomarkers on Earth-like planets. The team will also revisit early Earth models for a better understanding of the context of the origins of life, in the light of recent works on Earth formation, impact history and Solar evolution. The observable signatures of an ETP and its ability to sustain life are determined by atmospheric properties: chemistry, radiative transfer, climate. Although these processes are usually treated separately, they evolve in a tightly coupled scheme under the influence of astrophysical, geophysical and, if present, biological mechanisms. Eventually, realistic planetary environments will thus have to be modeled with self-consistent 3D tools, involving a multidisciplinary and international approach. Although ambitious by today's standards, such enterprise is a necessary counterpart of the planned ETP searches, and is required to study the discovered planets. Observatories like Darwin/TPF and ELTs will provide direct information on ETPs within 10-15 years. Ongoing transit searches (CoRoT, and Kepler), and radial-velocity surveys, are on the verge of detecting ETPs. In this context, E3ARTHS can become one of the cores in European theoretical research on ETPs, in close interaction with observation programs. Since his PhD, F. Selsis has developed his own research on ETPs, which already had important implications for the design of instruments for TEP search and characterization. His plan is now to take this research at the next level by creating a dedicated team that will integrate new tools such as 3D climate, photochemical and radiative transfer codes, produce virtual observations of ETPs, and study their potential for life.
Summary
This program is dedicated to the simulation and characterization of Extrasolar Terrestrial Planet (ETP) atmospheres. Thanks to new generation codes, the team E3ARTHS aims to provide a top expertise in a key domain of astrobiology: the origin, evolution and identification of habitable worlds, and the quest for biomarkers on Earth-like planets. The team will also revisit early Earth models for a better understanding of the context of the origins of life, in the light of recent works on Earth formation, impact history and Solar evolution. The observable signatures of an ETP and its ability to sustain life are determined by atmospheric properties: chemistry, radiative transfer, climate. Although these processes are usually treated separately, they evolve in a tightly coupled scheme under the influence of astrophysical, geophysical and, if present, biological mechanisms. Eventually, realistic planetary environments will thus have to be modeled with self-consistent 3D tools, involving a multidisciplinary and international approach. Although ambitious by today's standards, such enterprise is a necessary counterpart of the planned ETP searches, and is required to study the discovered planets. Observatories like Darwin/TPF and ELTs will provide direct information on ETPs within 10-15 years. Ongoing transit searches (CoRoT, and Kepler), and radial-velocity surveys, are on the verge of detecting ETPs. In this context, E3ARTHS can become one of the cores in European theoretical research on ETPs, in close interaction with observation programs. Since his PhD, F. Selsis has developed his own research on ETPs, which already had important implications for the design of instruments for TEP search and characterization. His plan is now to take this research at the next level by creating a dedicated team that will integrate new tools such as 3D climate, photochemical and radiative transfer codes, produce virtual observations of ETPs, and study their potential for life.
Max ERC Funding
719 759 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym GAMMARAYBINARIES
Project Exploring the gamma-ray sky: binaries, microquasars and their impact on understanding particle acceleration, relativistic winds and accretion/ejection phenomena in cosmic sources
Researcher (PI) Guillaume Dubus
Host Institution (HI) UNIVERSITE JOSEPH FOURIER GRENOBLE 1
Call Details Starting Grant (StG), PE7, ERC-2007-StG
Summary The most energetic photons in the universe are produced by poorly known processes, typically in the vicinity of neutron stars or black holes. The past couple of years have seen an increase in the number of known sources of very high energy gamma-ray radiation from a handful to almost 50, thanks to the European collaborations HESS and MAGIC. Many of those sources are pulsar wind nebulae, supernova remnants or active galactic nuclei. HESS and MAGIC have also discovered gamma-ray emission from binary systems, finding that some emit most of their radiation at the highest energies. Expectations are running high with the December launch of the GLAST space telescope which will provide daily all-sky information in high energy gamma-rays with a sensitivity comparable to that achieved in years by its predecessor. I propose to explore the exciting observational opportunities in high energy gamma-ray astronomy with an emphasis on non-thermal emission from compact binary sources. Binary systems are intriguing new laboratories to understand how particle acceleration works in cosmic sources. The physics of gamma-ray emitting binary systems is related to that in pulsar wind nebulae or in active galactic nuclei. High energy gamma-ray emission is the result of non-thermal, out-of-equilibrium processes that challenge our intuitions built upon everyday phenomena. The particles are billions of times more energetic than X-rays and can reach energies greater than those in particle accelerators. Binary systems offer a novel, constrained environment to study how the cosmic rays that pervade our Galaxy are accelerated and how non-thermal emission is related to the formation of relativistic jets from black holes (accretion/ejection). The study requires a combination of skills in multiwavelength observations, interdisciplinary experience with gamma-ray observational techniques originating from particle physics, and theoretical know-how in accretion and high energy phenomena.
Summary
The most energetic photons in the universe are produced by poorly known processes, typically in the vicinity of neutron stars or black holes. The past couple of years have seen an increase in the number of known sources of very high energy gamma-ray radiation from a handful to almost 50, thanks to the European collaborations HESS and MAGIC. Many of those sources are pulsar wind nebulae, supernova remnants or active galactic nuclei. HESS and MAGIC have also discovered gamma-ray emission from binary systems, finding that some emit most of their radiation at the highest energies. Expectations are running high with the December launch of the GLAST space telescope which will provide daily all-sky information in high energy gamma-rays with a sensitivity comparable to that achieved in years by its predecessor. I propose to explore the exciting observational opportunities in high energy gamma-ray astronomy with an emphasis on non-thermal emission from compact binary sources. Binary systems are intriguing new laboratories to understand how particle acceleration works in cosmic sources. The physics of gamma-ray emitting binary systems is related to that in pulsar wind nebulae or in active galactic nuclei. High energy gamma-ray emission is the result of non-thermal, out-of-equilibrium processes that challenge our intuitions built upon everyday phenomena. The particles are billions of times more energetic than X-rays and can reach energies greater than those in particle accelerators. Binary systems offer a novel, constrained environment to study how the cosmic rays that pervade our Galaxy are accelerated and how non-thermal emission is related to the formation of relativistic jets from black holes (accretion/ejection). The study requires a combination of skills in multiwavelength observations, interdisciplinary experience with gamma-ray observational techniques originating from particle physics, and theoretical know-how in accretion and high energy phenomena.
Max ERC Funding
794 752 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym GENOVIR
Project Adaptation of Virus Genomes to Insect Immunity
Researcher (PI) Elisabeth, Anne Herniou
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary How ecology shapes genomes is a key question to be addressed in the postgenomic era. A leading theory states that species evolve as groups of genomes adapting to particular ecological niches. Thus, shifts to a new ecological niche should be connected to genome divergence, and ultimately to the making of new species. So far we know little on how ecological adaptation affects genomes, because of the difficulty of simultaneously studying evolution at both ecological and whole genome levels. Insect viruses are ideally suited to study this question because their ecological niches are defined by their hosts and because of the nature of their genomes. The transmission of baculoviruses as groups of genomes sets them apart for studying the effect of niches on populations. Their molecular biology is also well understood, which makes them ideal to investigating the genetic and functional details of adaptation. They are thus unique for linking genome changes to ecological changes. Polydnaviruses have extraordinary genomes, domesticated by wasps to deliver molecular weapons to fight the immunity of their Lepidoptera hosts. Sequencing polydnavirus genomes therefore opens windows to understanding mutualism and how parasitic wasps have adapted to different hosts. Lastly, the diversity of insect viruses provides an exceptional opportunity to examine if different evolutionary lineages have converged toward similar genomic solutions to respond to similar immunity and why some lineages have diversified more than others. Studying virus adaptation to the immunity of different insect species will reveal how viral genomes have been shaped by the ecological niches of their host immunity. At the frontier of ecology and genomics GENOVIR, takes on the challenge of studying ecological adaptation at the level of whole genomes. The innovative application of cutting-edge molecular and genomic techniques to the interface with ecology will transform our understanding of evolution.
Summary
How ecology shapes genomes is a key question to be addressed in the postgenomic era. A leading theory states that species evolve as groups of genomes adapting to particular ecological niches. Thus, shifts to a new ecological niche should be connected to genome divergence, and ultimately to the making of new species. So far we know little on how ecological adaptation affects genomes, because of the difficulty of simultaneously studying evolution at both ecological and whole genome levels. Insect viruses are ideally suited to study this question because their ecological niches are defined by their hosts and because of the nature of their genomes. The transmission of baculoviruses as groups of genomes sets them apart for studying the effect of niches on populations. Their molecular biology is also well understood, which makes them ideal to investigating the genetic and functional details of adaptation. They are thus unique for linking genome changes to ecological changes. Polydnaviruses have extraordinary genomes, domesticated by wasps to deliver molecular weapons to fight the immunity of their Lepidoptera hosts. Sequencing polydnavirus genomes therefore opens windows to understanding mutualism and how parasitic wasps have adapted to different hosts. Lastly, the diversity of insect viruses provides an exceptional opportunity to examine if different evolutionary lineages have converged toward similar genomic solutions to respond to similar immunity and why some lineages have diversified more than others. Studying virus adaptation to the immunity of different insect species will reveal how viral genomes have been shaped by the ecological niches of their host immunity. At the frontier of ecology and genomics GENOVIR, takes on the challenge of studying ecological adaptation at the level of whole genomes. The innovative application of cutting-edge molecular and genomic techniques to the interface with ecology will transform our understanding of evolution.
Max ERC Funding
1 000 000 €
Duration
Start date: 2008-10-01, End date: 2014-06-30
Project acronym GEVM
Project Genetic and Environmental Variation of Memory phases
Researcher (PI) Frederic Mery
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary Memory (i.e. the ability to store and retrieve information) plays a crucial role in the development of an animal’s behavior within its lifespan and is often important for its survival and reproductive success. Memory is itself a product of evolution and the degree to which information is maintained in the brain varies among species and among different types of behavior. Findings from vertebrate behavioral pharmacology have challenged the traditional view of memory formation as a direct flow from short-term to long-term storage. Evidence points instead to an intricate, multiphase pathway of memory consolidation. Different components of memory emerge at different times after the event to be memorized takes place. In addition, their duration and times of onset can vary with different tasks and species If variations in memory capacities have been observed among closely-related species, the relationship between environmental conditions and evolution of these capacities have only been rarely studied despite the importance of this topic in the understanding of the evolution of behavior. I propose an experimental approach using Drosophila as a model system. This project concentrates on: Part 1: Genetic variation of the memory phases Part 2: Effect of the environmental conditions on the development of memory Part 3: fitness cost of memory Part 4: Consolidation, Reconsolidation and Extinction: similar or separate processes?
Summary
Memory (i.e. the ability to store and retrieve information) plays a crucial role in the development of an animal’s behavior within its lifespan and is often important for its survival and reproductive success. Memory is itself a product of evolution and the degree to which information is maintained in the brain varies among species and among different types of behavior. Findings from vertebrate behavioral pharmacology have challenged the traditional view of memory formation as a direct flow from short-term to long-term storage. Evidence points instead to an intricate, multiphase pathway of memory consolidation. Different components of memory emerge at different times after the event to be memorized takes place. In addition, their duration and times of onset can vary with different tasks and species If variations in memory capacities have been observed among closely-related species, the relationship between environmental conditions and evolution of these capacities have only been rarely studied despite the importance of this topic in the understanding of the evolution of behavior. I propose an experimental approach using Drosophila as a model system. This project concentrates on: Part 1: Genetic variation of the memory phases Part 2: Effect of the environmental conditions on the development of memory Part 3: fitness cost of memory Part 4: Consolidation, Reconsolidation and Extinction: similar or separate processes?
Max ERC Funding
534 000 €
Duration
Start date: 2008-09-01, End date: 2011-08-31
Project acronym HCV_IMMUNOLOGY
Project The paradoxical role of type I interferons in Hepatitis C disease pathogenesis and treatment
Researcher (PI) Matthew Albert
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary Hepatitis C virus (HCV) presents a significant public health problem with nearly 200 million infected people worldwide. Over the past three years, we have developed partnerships with clinicians and epidemiologists so that we can achieve better insight into immune pathogenesis of both acute and chronic HCV infection. My newly created research unit is committed to defining the complex interplay between virus and host from the perspective of type I interferons (IFNs) and IFN induced gene products. Furthermore, we aim to identify biomarkers predictive of viral clearance that could help identify, pre-treatment, which individuals will respond to their IFNα / ribavirin therapy. Specifically, we aim to: I. To define the role of IFN and IFN-induced genes in HCV clearance. This aim will utilize patient samples to define the role of endogenously produced IFNs in the clearance of HCV during acute infection and the paradoxical role they play in making chronically infected patients resistant to their exogenous IFN therapy. II. To characterize the effect of IFN and INF-induced gene products in the cross-priming of CD8+ T cells. This aim is based on our evidence that HCV-reactive CD8+ T cells are activated by an indirect pathway called cross-presentation and our recent data, which illustrates the complex ways in which type I IFNs can regulate this antigen presentation pathway. III. To determine the in vivo pro- and counter-inflammatory effect of IFN and INF-induced gene products in the cross-priming of CD8+ T cells. This aspect of the project will utilize mouse models to test our hypotheses regarding HCV disease pathogenesis. Our work and the studies outlined in this proposal will help push forward our understanding of the HCV disease pathogenesis and lead to the development of new diagnostic tools as well as strategies for improving upon existing therapeutic strategies.
Summary
Hepatitis C virus (HCV) presents a significant public health problem with nearly 200 million infected people worldwide. Over the past three years, we have developed partnerships with clinicians and epidemiologists so that we can achieve better insight into immune pathogenesis of both acute and chronic HCV infection. My newly created research unit is committed to defining the complex interplay between virus and host from the perspective of type I interferons (IFNs) and IFN induced gene products. Furthermore, we aim to identify biomarkers predictive of viral clearance that could help identify, pre-treatment, which individuals will respond to their IFNα / ribavirin therapy. Specifically, we aim to: I. To define the role of IFN and IFN-induced genes in HCV clearance. This aim will utilize patient samples to define the role of endogenously produced IFNs in the clearance of HCV during acute infection and the paradoxical role they play in making chronically infected patients resistant to their exogenous IFN therapy. II. To characterize the effect of IFN and INF-induced gene products in the cross-priming of CD8+ T cells. This aim is based on our evidence that HCV-reactive CD8+ T cells are activated by an indirect pathway called cross-presentation and our recent data, which illustrates the complex ways in which type I IFNs can regulate this antigen presentation pathway. III. To determine the in vivo pro- and counter-inflammatory effect of IFN and INF-induced gene products in the cross-priming of CD8+ T cells. This aspect of the project will utilize mouse models to test our hypotheses regarding HCV disease pathogenesis. Our work and the studies outlined in this proposal will help push forward our understanding of the HCV disease pathogenesis and lead to the development of new diagnostic tools as well as strategies for improving upon existing therapeutic strategies.
Max ERC Funding
1 098 000 €
Duration
Start date: 2009-01-01, End date: 2014-06-30
Project acronym ISCATAXIA
Project Unraveling the molecular mechanisms leading to cellular dysfunction in diseases linked to defects in mitochondrial iron-sulfur cluster metabolism
Researcher (PI) Hélène Monique Sadoulet Puccio
Host Institution (HI) CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE
Call Details Starting Grant (StG), LS4, ERC-2007-StG
Summary The project aims at unraveling the molecular pathophysiology of recessive ataxias, a heterogeneous set of severely disabling neurodegenerative disorders due to loss of function of proteins involved either in mitochondrial/metabolic pathways or DNA repair. Friedreich ataxia, the most common form, is due to partial loss of function of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biogenesis. Furthermore, the rare X-linked sideroblastic anemia with cerebellar ataxia is caused by mutation in ABCb7, an ATP-binding cassette transporter of the mitochondrial inner membrane necessary for cytosolic ISC export. ISC are versatile co-factors of proteins involved in electron transport, enzyme catalysis and regulation of gene expression. The synthesis and insertion of ISC into apoproteins involve complex machineries that are still poorly understood in the mammalian cell. The objectives of this proposal are: 1) to elucidate ISC biogenesis and metabolism in the mammalian cell, with an emphasis on the role of frataxin and ABCb7; 2) to better understand the molecular pathways that are involved in neuronal dysfunction due to defects in mitochondrial ISC metabolism. These objectives will be accomplished by a multidisciplinary approach combining molecular and biochemical approaches to study the ISC assembly machineries, bioinformatic and proteomic studies to identify new Fe-S proteins, the development and pathological analysis of animal and cellular models to dissect the molecular mechanisms, and transcriptomic analysis to uncover the common pathways among recessive ataxias. A specific focus of the proposal will be the involvement of DNA damage response pathways in neuronal dysfunction, as several DNA repair enzymes have recently been identified as Fe-S proteins and thus might be directly affected by frataxin and ABCb7 deficiency. This proposal should lead to the identification of different pathways for therapeutic intervention for these devastating disorders.
Summary
The project aims at unraveling the molecular pathophysiology of recessive ataxias, a heterogeneous set of severely disabling neurodegenerative disorders due to loss of function of proteins involved either in mitochondrial/metabolic pathways or DNA repair. Friedreich ataxia, the most common form, is due to partial loss of function of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biogenesis. Furthermore, the rare X-linked sideroblastic anemia with cerebellar ataxia is caused by mutation in ABCb7, an ATP-binding cassette transporter of the mitochondrial inner membrane necessary for cytosolic ISC export. ISC are versatile co-factors of proteins involved in electron transport, enzyme catalysis and regulation of gene expression. The synthesis and insertion of ISC into apoproteins involve complex machineries that are still poorly understood in the mammalian cell. The objectives of this proposal are: 1) to elucidate ISC biogenesis and metabolism in the mammalian cell, with an emphasis on the role of frataxin and ABCb7; 2) to better understand the molecular pathways that are involved in neuronal dysfunction due to defects in mitochondrial ISC metabolism. These objectives will be accomplished by a multidisciplinary approach combining molecular and biochemical approaches to study the ISC assembly machineries, bioinformatic and proteomic studies to identify new Fe-S proteins, the development and pathological analysis of animal and cellular models to dissect the molecular mechanisms, and transcriptomic analysis to uncover the common pathways among recessive ataxias. A specific focus of the proposal will be the involvement of DNA damage response pathways in neuronal dysfunction, as several DNA repair enzymes have recently been identified as Fe-S proteins and thus might be directly affected by frataxin and ABCb7 deficiency. This proposal should lead to the identification of different pathways for therapeutic intervention for these devastating disorders.
Max ERC Funding
1 449 924 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym MICROGLIA AND AMD
Project Subretinal Microglia accumulation play a decisive role in the development of Age-related Macular Degeneration
Researcher (PI) Florian Sennlaub
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS6, ERC-2007-StG
Summary Age-related macular degeneration (AMD) is the leading cause of vision loss in the Europe. New anti-angiogenic therapies of AMD do not treat the neurodegenerative aspect of AMD. Recent evidence suggests an implication of inflammatory mediators in AMD. We have focused our interest on the potential role of chemokines (Ch) and microglial cells (MC) in this condition. Our data concerning the chemokine receptor (CR) CX3CR1, indicates that (i) CR are expressed on MCs in human and mice; (ii) CR-positive MC accumulate in affected areas of the macula in human AMD, (iii) CX3CR1 deficient mice develop age dependent subretinal MC accumulation, Drusen formation, retinal degeneration and exacerbated neovascularization, similarly to AMD. Our data suggests an important role of subretinal MC accumulation in the development of AMD. We hypothesize that (1) function altering polymorphisms in genes of Ch pathways are associated with AMD, that (2) this pathway dysfunction leads to MC accumulate in the subretinal space with age and (3) the consequential prolonged MC presence in the subretinal space leads to cardinal features of AMD (Drusen, retinal degeneration, neovascularization). Therefore we believe that decreasing subretinal MCs or interfering with their neurotoxic and angiogenic factors will inhibit AMD development. Our specific aim is to study (1) polymorphisms of Ch pathways in AMD and controls, (2) determine the Ch pathways involved in the recruitment and accumulation of MCs to the subretinal space, (3) determine the implication of MC in Drusen formation, retinal degeneration and neovascularization and characterize the implicated molecular mediators and (4) test the identified mediators of microglial cell neurotoxicity and angiogenicity as drug targets in AMD models. The aim of this work, from clinical polymorphism studies to transgenic mouse models, is to propose new mechanisms in the pathogenesis of AMD and to develop novel therapeutic strategies for the treatment of AMD.
Summary
Age-related macular degeneration (AMD) is the leading cause of vision loss in the Europe. New anti-angiogenic therapies of AMD do not treat the neurodegenerative aspect of AMD. Recent evidence suggests an implication of inflammatory mediators in AMD. We have focused our interest on the potential role of chemokines (Ch) and microglial cells (MC) in this condition. Our data concerning the chemokine receptor (CR) CX3CR1, indicates that (i) CR are expressed on MCs in human and mice; (ii) CR-positive MC accumulate in affected areas of the macula in human AMD, (iii) CX3CR1 deficient mice develop age dependent subretinal MC accumulation, Drusen formation, retinal degeneration and exacerbated neovascularization, similarly to AMD. Our data suggests an important role of subretinal MC accumulation in the development of AMD. We hypothesize that (1) function altering polymorphisms in genes of Ch pathways are associated with AMD, that (2) this pathway dysfunction leads to MC accumulate in the subretinal space with age and (3) the consequential prolonged MC presence in the subretinal space leads to cardinal features of AMD (Drusen, retinal degeneration, neovascularization). Therefore we believe that decreasing subretinal MCs or interfering with their neurotoxic and angiogenic factors will inhibit AMD development. Our specific aim is to study (1) polymorphisms of Ch pathways in AMD and controls, (2) determine the Ch pathways involved in the recruitment and accumulation of MCs to the subretinal space, (3) determine the implication of MC in Drusen formation, retinal degeneration and neovascularization and characterize the implicated molecular mediators and (4) test the identified mediators of microglial cell neurotoxicity and angiogenicity as drug targets in AMD models. The aim of this work, from clinical polymorphism studies to transgenic mouse models, is to propose new mechanisms in the pathogenesis of AMD and to develop novel therapeutic strategies for the treatment of AMD.
Max ERC Funding
1 560 000 €
Duration
Start date: 2008-09-01, End date: 2013-08-31