Project acronym 2-HIT
Project Genetic interaction networks: From C. elegans to human disease
Researcher (PI) Ben Lehner
Host Institution (HI) FUNDACIO CENTRE DE REGULACIO GENOMICA
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary Most hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.
Summary
Most hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.
Max ERC Funding
1 100 000 €
Duration
Start date: 2008-09-01, End date: 2014-04-30
Project acronym BCLYM
Project Molecular mechanisms of mature B cell lymphomagenesis
Researcher (PI) Almudena Ramiro
Host Institution (HI) CENTRO NACIONAL DE INVESTIGACIONESCARDIOVASCULARES CARLOS III (F.S.P.)
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary Most of the lymphomas diagnosed in the western world are originated from mature B cells. The hallmark of these malignancies is the presence of recurrent chromosome translocations that usually involve the immunoglobulin loci and a proto-oncogene. As a result of the translocation event the proto-oncogene becomes deregulated under the influence of immunoglobulin cis sequences thus playing an important role in the etiology of the disease. Upon antigen encounter mature B cells engage in the germinal center reaction, a complex differentiation program of critical importance to the development of the secondary immune response. The germinal center reaction entails the somatic remodelling of immunoglobulin genes by the somatic hypermutation and class switch recombination reactions, both of which are triggered by Activation Induced Deaminase (AID). We have previously shown that AID also initiates lymphoma-associated c-myc/IgH chromosome translocations. In addition, the germinal center reaction involves a fine-tuned balance between intense B cell proliferation and program cell death. This environment seems to render B cells particularly vulnerable to malignant transformation. We aim at studying the molecular events responsible for B cell susceptibility to lymphomagenesis from two perspectives. First, we will address the role of AID in the generation of lymphomagenic lesions in the context of AID specificity and transcriptional activation. Second, we will approach the regulatory function of microRNAs of AID-dependent, germinal center events. The proposal aims at the molecular understanding of a process that lies in the interface of immune regulation and oncogenic transformation and therefore the results will have profound implications both to basic and clinical understanding of lymphomagenesis.
Summary
Most of the lymphomas diagnosed in the western world are originated from mature B cells. The hallmark of these malignancies is the presence of recurrent chromosome translocations that usually involve the immunoglobulin loci and a proto-oncogene. As a result of the translocation event the proto-oncogene becomes deregulated under the influence of immunoglobulin cis sequences thus playing an important role in the etiology of the disease. Upon antigen encounter mature B cells engage in the germinal center reaction, a complex differentiation program of critical importance to the development of the secondary immune response. The germinal center reaction entails the somatic remodelling of immunoglobulin genes by the somatic hypermutation and class switch recombination reactions, both of which are triggered by Activation Induced Deaminase (AID). We have previously shown that AID also initiates lymphoma-associated c-myc/IgH chromosome translocations. In addition, the germinal center reaction involves a fine-tuned balance between intense B cell proliferation and program cell death. This environment seems to render B cells particularly vulnerable to malignant transformation. We aim at studying the molecular events responsible for B cell susceptibility to lymphomagenesis from two perspectives. First, we will address the role of AID in the generation of lymphomagenic lesions in the context of AID specificity and transcriptional activation. Second, we will approach the regulatory function of microRNAs of AID-dependent, germinal center events. The proposal aims at the molecular understanding of a process that lies in the interface of immune regulation and oncogenic transformation and therefore the results will have profound implications both to basic and clinical understanding of lymphomagenesis.
Max ERC Funding
1 596 000 €
Duration
Start date: 2008-12-01, End date: 2014-11-30
Project acronym BIOMOTIV
Project Why do we do what we do? Biological, psychological and computational bases of motivation
Researcher (PI) Mathias Pessiglione
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary We are largely unaware of our own motives. Understanding our motives can be reduced to knowing how we form goals and these goals translate into behavior. Goals can be defined as pleasurable situations that we particularly value and that we intend to reach. Recent investigation in the emerging field of neuro-economics has put forward a neuronal network constituting a brain valuation system (BVS). We wish to build a more comprehensive account of motivational processes, investigating not only valuation and choice but also effort (how much energy we would spend to attain a goal). More specifically, our aims are to better describe 1) how the brain assigns values to various objects and actions, 2) how values depend on parameters such as reward magnitude, probability, delay and cost, 3) how values are affected by social contexts, 4) how values are modified through learning and 5) how values influence the brain systems (perceptual, cognitive and motor) that underpin behavioral performance. To these aims, we would combine three approaches: 1) human cognitive neuroscience, which is central as we ultimately wish to understand ourselves, as well as human pathological conditions where motivation is either deficient (apathy) or out of control (compulsion), 2) primate neurophysiology, which is essential to describe information processing at the single-unit level and to derive causality by observing behavioral consequences of brain manipulations, 3) computational modeling, which is mandatory to link quantitatively the different descriptions levels (single-unit recordings, local field potentials, regional BOLD signal, vegetative manifestations and motor outputs). A bayesian framework will be developed to infer from experimental measures the subjects prior beliefs and value functions. We believe that our team, bringing together three complementary perspectives on motivation within a clinical environment, would represent a unique education and research center in Europe.
Summary
We are largely unaware of our own motives. Understanding our motives can be reduced to knowing how we form goals and these goals translate into behavior. Goals can be defined as pleasurable situations that we particularly value and that we intend to reach. Recent investigation in the emerging field of neuro-economics has put forward a neuronal network constituting a brain valuation system (BVS). We wish to build a more comprehensive account of motivational processes, investigating not only valuation and choice but also effort (how much energy we would spend to attain a goal). More specifically, our aims are to better describe 1) how the brain assigns values to various objects and actions, 2) how values depend on parameters such as reward magnitude, probability, delay and cost, 3) how values are affected by social contexts, 4) how values are modified through learning and 5) how values influence the brain systems (perceptual, cognitive and motor) that underpin behavioral performance. To these aims, we would combine three approaches: 1) human cognitive neuroscience, which is central as we ultimately wish to understand ourselves, as well as human pathological conditions where motivation is either deficient (apathy) or out of control (compulsion), 2) primate neurophysiology, which is essential to describe information processing at the single-unit level and to derive causality by observing behavioral consequences of brain manipulations, 3) computational modeling, which is mandatory to link quantitatively the different descriptions levels (single-unit recordings, local field potentials, regional BOLD signal, vegetative manifestations and motor outputs). A bayesian framework will be developed to infer from experimental measures the subjects prior beliefs and value functions. We believe that our team, bringing together three complementary perspectives on motivation within a clinical environment, would represent a unique education and research center in Europe.
Max ERC Funding
1 346 000 €
Duration
Start date: 2011-03-01, End date: 2016-08-31
Project acronym CBSCS
Project Physiology of the adult carotid body stem cell niche
Researcher (PI) Ricardo Pardal
Host Institution (HI) UNIVERSIDAD DE SEVILLA
Call Details Starting Grant (StG), LS3, ERC-2010-StG_20091118
Summary The discovery of adult neural stem cells (NSCs) has broaden our view of the physiological plasticity of the nervous system,
and has opened new perspectives on the possibility of tissue regeneration and repair in the brain. NSCs reside in specialized
niches in the adult mammalian nervous system, where they are exposed to specific paracrine signals regulating their
behavior. These neural progenitors are generally in a quiescent state within their niche, and they activate their proliferation
depending on tissue regenerative and growth needs. Understanding the mechanisms by which NSCs enter and exit the
quiescent state is crucial for the comprehension of the physiology of the adult nervous system. In this project we will study
the behavior of a specific subpopulation of adult neural stem cells recently described by our group in the carotid body (CB).
This small organ constitutes the most important chemosensor of the peripheral nervous system and has neuronal glomus
cells responsible for the chemosensing, and glia-like sustentacular cells which were thought to have just a supportive role.
We recently described that these sustentacular cells are dormant stem cells able to activate their proliferation in response to a
physiological stimulus like hypoxia, and to differentiate into new glomus cells necessary for the adaptation of the organ.
Due to our precise experimental control of the activation and deactivation of the CB neurogenic niche, we believe the CB is
an ideal model to study fundamental questions about adult neural stem cell physiology and the interaction with the niche. We
propose to study the cellular and molecular mechanisms by which these carotid body stem cells enter and exit the quiescent
state, which will help us understand the physiology of adult neurogenic niches. Likewise, understanding this neurogenic
process will improve the efficacy of using glomus cells for cell therapy against neurological disease, and might help us
understand some neural tumors.
Summary
The discovery of adult neural stem cells (NSCs) has broaden our view of the physiological plasticity of the nervous system,
and has opened new perspectives on the possibility of tissue regeneration and repair in the brain. NSCs reside in specialized
niches in the adult mammalian nervous system, where they are exposed to specific paracrine signals regulating their
behavior. These neural progenitors are generally in a quiescent state within their niche, and they activate their proliferation
depending on tissue regenerative and growth needs. Understanding the mechanisms by which NSCs enter and exit the
quiescent state is crucial for the comprehension of the physiology of the adult nervous system. In this project we will study
the behavior of a specific subpopulation of adult neural stem cells recently described by our group in the carotid body (CB).
This small organ constitutes the most important chemosensor of the peripheral nervous system and has neuronal glomus
cells responsible for the chemosensing, and glia-like sustentacular cells which were thought to have just a supportive role.
We recently described that these sustentacular cells are dormant stem cells able to activate their proliferation in response to a
physiological stimulus like hypoxia, and to differentiate into new glomus cells necessary for the adaptation of the organ.
Due to our precise experimental control of the activation and deactivation of the CB neurogenic niche, we believe the CB is
an ideal model to study fundamental questions about adult neural stem cell physiology and the interaction with the niche. We
propose to study the cellular and molecular mechanisms by which these carotid body stem cells enter and exit the quiescent
state, which will help us understand the physiology of adult neurogenic niches. Likewise, understanding this neurogenic
process will improve the efficacy of using glomus cells for cell therapy against neurological disease, and might help us
understand some neural tumors.
Max ERC Funding
1 476 000 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
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 CLR SENSING NECROSIS
Project Immune Functions of Myeloid Syk-coupled C-type Lectin Receptors Sensing Necrosis
Researcher (PI) David Sancho Madrid
Host Institution (HI) CENTRO NACIONAL DE INVESTIGACIONESCARDIOVASCULARES CARLOS III (F.S.P.)
Call Details Starting Grant (StG), LS6, ERC-2010-StG_20091118
Summary Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity in infection-free situations, such as autoimmunity or therapy-induced tumour rejection. Recently, we and others have identified the myeloid C-type lectin receptors (CLRs) CLEC9A (DNGR-1), in DC, and Mincle, in macrophages, as receptors for necrotic cells that can signal via the Syk kinase. Previous studies on similar Syk-coupled CLRs showed that Dectin-1 and Dectin-2 can induce innate and adaptive immune responses. We thus hypothesise that recognition of cell death by myeloid Syk-coupled CLRs is at the root of immune pathologies associated with accumulation of dead cells. The overall objective of this proposal is to investigate necrosis sensing by myeloid cells as a trigger of immunity and to study the underlying molecular mechanisms. Our first goal is to characterise signalling and gene induction via CLEC9A as a model necrosis receptor in DCs. Second, we will investigate the role of myeloid Syk-coupled necrosis-sensing CLRs in animal models of atherosclerosis, lupus and immunity to chemotherapy-treated tumours. Our preliminary data suggest that additional receptors can couple necrosis recognition to the Syk pathway in DC; thus, our third aim is to identify novel myeloid Syk-coupled receptors for necrotic cells. Characterisation of the outcomes of sensing necrosis by myeloid Syk-coupled receptors and their effect on the proposed pathologies promises to identify new mechanisms and targets for the treatment of these diseases.
Summary
Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity in infection-free situations, such as autoimmunity or therapy-induced tumour rejection. Recently, we and others have identified the myeloid C-type lectin receptors (CLRs) CLEC9A (DNGR-1), in DC, and Mincle, in macrophages, as receptors for necrotic cells that can signal via the Syk kinase. Previous studies on similar Syk-coupled CLRs showed that Dectin-1 and Dectin-2 can induce innate and adaptive immune responses. We thus hypothesise that recognition of cell death by myeloid Syk-coupled CLRs is at the root of immune pathologies associated with accumulation of dead cells. The overall objective of this proposal is to investigate necrosis sensing by myeloid cells as a trigger of immunity and to study the underlying molecular mechanisms. Our first goal is to characterise signalling and gene induction via CLEC9A as a model necrosis receptor in DCs. Second, we will investigate the role of myeloid Syk-coupled necrosis-sensing CLRs in animal models of atherosclerosis, lupus and immunity to chemotherapy-treated tumours. Our preliminary data suggest that additional receptors can couple necrosis recognition to the Syk pathway in DC; thus, our third aim is to identify novel myeloid Syk-coupled receptors for necrotic cells. Characterisation of the outcomes of sensing necrosis by myeloid Syk-coupled receptors and their effect on the proposed pathologies promises to identify new mechanisms and targets for the treatment of these diseases.
Max ERC Funding
1 297 671 €
Duration
Start date: 2010-12-01, End date: 2016-08-31
Project acronym COMFUS
Project Computational Methods for Fusion Technology
Researcher (PI) Santiago Ignacio Badia Rodríguez
Host Institution (HI) CENTRE INTERNACIONAL DE METODES NUMERICS EN ENGINYERIA
Call Details Starting Grant (StG), PE8, ERC-2010-StG_20091028
Summary The simulation of multidisciplinary applications use very often a combination of heterogeneous and disjoint numerical techniques that are hard to put together by the user, and whose mathematical foundation is obscure. An example of this situation is the numerical modeling of the physical processes taking place in nuclear fusion reactors. This problem, which can be modeled by a set of partial differential equations, is extremely challenging. It involves (essentially) fluid mechanics, electromagnetics, thermal radiation and neutronics. The most common numerical approaches to each of these problems separately are very different and their coupling is a hard and inefficient task.
Our main objective in this proposal is to develop and analyze a unified numerical framework based on stabilized finite element methods based on multi-scale decompositions capable to simulate all the physical processes taking place in nuclear fusion technology. The project aims at giving a substantial contribution to the numerical approximation of every physical process as well as efficient coupling techniques for the multiphysics problems.
The development of the numerical formulations we propose and their application require mastering different physics, designing numerical approximations for these different physical problems, analyzing mathematically the resulting methods, implementing them in an efficient way in parallel platforms and understanding the results and drawing conclusions, both from a physical and from an engineering perspective. Advanced research in physical modeling, numerical approximations, mathematical analysis and computer implementation are the keys to meeting these objectives.
The successful implementation of the project will provide advanced numerical techniques for the simulation of the processes taking place in a fusion reactor. A deliverable product of the project will be a unified finite element software package that will be an extremely valuable tool.
Summary
The simulation of multidisciplinary applications use very often a combination of heterogeneous and disjoint numerical techniques that are hard to put together by the user, and whose mathematical foundation is obscure. An example of this situation is the numerical modeling of the physical processes taking place in nuclear fusion reactors. This problem, which can be modeled by a set of partial differential equations, is extremely challenging. It involves (essentially) fluid mechanics, electromagnetics, thermal radiation and neutronics. The most common numerical approaches to each of these problems separately are very different and their coupling is a hard and inefficient task.
Our main objective in this proposal is to develop and analyze a unified numerical framework based on stabilized finite element methods based on multi-scale decompositions capable to simulate all the physical processes taking place in nuclear fusion technology. The project aims at giving a substantial contribution to the numerical approximation of every physical process as well as efficient coupling techniques for the multiphysics problems.
The development of the numerical formulations we propose and their application require mastering different physics, designing numerical approximations for these different physical problems, analyzing mathematically the resulting methods, implementing them in an efficient way in parallel platforms and understanding the results and drawing conclusions, both from a physical and from an engineering perspective. Advanced research in physical modeling, numerical approximations, mathematical analysis and computer implementation are the keys to meeting these objectives.
The successful implementation of the project will provide advanced numerical techniques for the simulation of the processes taking place in a fusion reactor. A deliverable product of the project will be a unified finite element software package that will be an extremely valuable tool.
Max ERC Funding
1 320 000 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
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 COSIRIS
Project Investigating the terrestrial carbon and water cycles with a multi-tracer approach
Researcher (PI) Ulrike Seibt
Host Institution (HI) UNIVERSITE PIERRE ET MARIE CURIE - PARIS 6
Call Details Starting Grant (StG), PE8, ERC-2007-StG
Summary The aim of COSIRIS is to isolate the simultaneous fluxes of photosynthesis and respiration of the terrestrial biosphere. With explicit knowledge of the component fluxes, we will: 1) test process based models of photosynthesis and respiration, 2) determine the sensitivity of each flux to environmental conditions, and 3) derive predictions of their responses to climate change. Specifically, COSIRIS aims to build a research facility to integrate a new tracer, carbonyl sulfide (COS) with CO2, water and their stable isotopes in a multi-tracer framework as a tool to separately investigate photosynthesis and respiration. In terrestrial ecosystems, CO2 is often taken up and released at the same time. Similar to CO2, COS is taken up during photosynthesis, but unlike CO2, concurrent COS emissions are small. Parallel COS and CO2 measurements thus promise to provide estimates of gross photosynthetic fluxes – impossible to measure directly at scales larger than a few leaves. The use of COS to derive CO2 fluxes has not been verified yet, but enough is known about their parallel pathways to suggest that COS, CO2 and its isotopes can be combined to yield powerful and unique constraints on gross carbon fluxes. COSIRIS will develop the expertise necessary to achieve this goal by providing: 1. an in-depth analysis of processes involved in COS uptake by vegetation, and of potentially interfering influences such as uptake by soil, 2. a novel process-based multi-tracer modelling framework of COS, CO2, water and their isotopes at the ecosystem scale, 3. extensive datasets on concurrent fluctuations of COS, CO2, water and their isotopes in ecosystems. This innovative approach promises advances in understanding and determining gross carbon fluxes at ecosystem to continental scales, particularly their variations in response to climate anomalies.
Summary
The aim of COSIRIS is to isolate the simultaneous fluxes of photosynthesis and respiration of the terrestrial biosphere. With explicit knowledge of the component fluxes, we will: 1) test process based models of photosynthesis and respiration, 2) determine the sensitivity of each flux to environmental conditions, and 3) derive predictions of their responses to climate change. Specifically, COSIRIS aims to build a research facility to integrate a new tracer, carbonyl sulfide (COS) with CO2, water and their stable isotopes in a multi-tracer framework as a tool to separately investigate photosynthesis and respiration. In terrestrial ecosystems, CO2 is often taken up and released at the same time. Similar to CO2, COS is taken up during photosynthesis, but unlike CO2, concurrent COS emissions are small. Parallel COS and CO2 measurements thus promise to provide estimates of gross photosynthetic fluxes – impossible to measure directly at scales larger than a few leaves. The use of COS to derive CO2 fluxes has not been verified yet, but enough is known about their parallel pathways to suggest that COS, CO2 and its isotopes can be combined to yield powerful and unique constraints on gross carbon fluxes. COSIRIS will develop the expertise necessary to achieve this goal by providing: 1. an in-depth analysis of processes involved in COS uptake by vegetation, and of potentially interfering influences such as uptake by soil, 2. a novel process-based multi-tracer modelling framework of COS, CO2, water and their isotopes at the ecosystem scale, 3. extensive datasets on concurrent fluctuations of COS, CO2, water and their isotopes in ecosystems. This innovative approach promises advances in understanding and determining gross carbon fluxes at ecosystem to continental scales, particularly their variations in response to climate anomalies.
Max ERC Funding
1 822 000 €
Duration
Start date: 2008-07-01, End date: 2014-10-31
Project acronym CRC PROGRAMME
Project Dissecting the roles of the beta-catenin and Tcf genetic programmes during colorectal cancer progression
Researcher (PI) Eduard Batlle Gomez
Host Institution (HI) FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Call Details Starting Grant (StG), LS6, ERC-2007-StG
Summary Most colorectal cancers (CRCs) are initiated by activating mutations in components of the Wnt signalling pathway. Physiological Wnt signals are required for the specification and maintenance of the stem and progenitor cell compartments of the intestinal crypts. We demonstrated that early colorectal lesions exhibit a constitutive Wnt target gene programme, which is very similar to that of normal intestinal stem and progenitor cells. We originally proposed that colorectal adenomas behave as clusters of intestinal cells locked into a constitutive crypt progenitor phenotype. Given the prevalence of Wnt signalling mutations in CRC, an outstanding endeavour is the characterization of the similarities and differences in the instructions dictated by beta-catenin and Tcf to normal intestinal cells vs. CRC cells. Here, we propose to systematically compare and catalogue the beta-catenin/Tcf genetic programmes in intestinal progenitor/stem cells, intestinal adenomas and late CRCs. Transcriptomic analysis of isolated normal progenitor cells and tumor cell populations combined with bioinformatic analysis of gene regulatory networks will allow us to workout the hierarchical interactions downstream of beta-catenin and Tcf. Moreover, functional analysis of key beta-catenin/Tcf target genes using genetically modified mice models will help us to pinpoint which Wnt-controlled functions are essential for tumor maintenance and progression in vivo. Moreover, we seek to understand the tumor suppressor role of EphB2 and EphB3 receptors, two beta-catenin/Tcf target genes in normal crypts and benign colorectal adenomas, that block cancer progression by compartmentalizing tumor cells at the onset of CRC. Overall, our results will shed light on the relationship between stem/progenitor cells and cancer and hold potential for the future development of both therapeutic and diagnostic tools.
Summary
Most colorectal cancers (CRCs) are initiated by activating mutations in components of the Wnt signalling pathway. Physiological Wnt signals are required for the specification and maintenance of the stem and progenitor cell compartments of the intestinal crypts. We demonstrated that early colorectal lesions exhibit a constitutive Wnt target gene programme, which is very similar to that of normal intestinal stem and progenitor cells. We originally proposed that colorectal adenomas behave as clusters of intestinal cells locked into a constitutive crypt progenitor phenotype. Given the prevalence of Wnt signalling mutations in CRC, an outstanding endeavour is the characterization of the similarities and differences in the instructions dictated by beta-catenin and Tcf to normal intestinal cells vs. CRC cells. Here, we propose to systematically compare and catalogue the beta-catenin/Tcf genetic programmes in intestinal progenitor/stem cells, intestinal adenomas and late CRCs. Transcriptomic analysis of isolated normal progenitor cells and tumor cell populations combined with bioinformatic analysis of gene regulatory networks will allow us to workout the hierarchical interactions downstream of beta-catenin and Tcf. Moreover, functional analysis of key beta-catenin/Tcf target genes using genetically modified mice models will help us to pinpoint which Wnt-controlled functions are essential for tumor maintenance and progression in vivo. Moreover, we seek to understand the tumor suppressor role of EphB2 and EphB3 receptors, two beta-catenin/Tcf target genes in normal crypts and benign colorectal adenomas, that block cancer progression by compartmentalizing tumor cells at the onset of CRC. Overall, our results will shed light on the relationship between stem/progenitor cells and cancer and hold potential for the future development of both therapeutic and diagnostic tools.
Max ERC Funding
1 602 817 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
