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 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 CHROMOREPAIR
Project Genome Maintenance in the Context of Chromatin
Researcher (PI) Oscar Fernández-Capetillo Ruiz
Host Institution (HI) FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary With the availability of the essentially complete sequence of the human genome, as well as a rapid development of massive sequencing techniques, the research efforts to understand genetics and disease from a cis standpoint will soon reach an endpoint. However, our emerging knowledge of gene regulation networks reveals that epigenetic regulation of the hereditary information plays crucial roles in various biological events through its influence on processes such as transcription, DNA replication and chromosome architecture. Another scenario in which the control of chromatin structure is crucial is the repair of lesions in genomic DNA. There is mounting evidence, particularly from model organisms such as Saccharomyces cerevisiae, that histone modifying enzymes (acetylases, deacetylases, kinases, …) are essential components of the machinery that maintains genome integrity and thereby guards against cancer, degenerative diseases and ageing. However, little is known about the specific “code” of histone tail modifications that coordinate DNA repair, and the impact that an aberrant “histone code” may have on human health. In CHROMOREPAIR we will systematically analyze the chromatin remodelling process that undergoes at DNA lesions and evaluate the impact that chromatin alterations have on the access, signaling and repair of DNA damage. Furthermore, we propose to translate our in vitro knowledge to the development of mouse models that help us evaluate how modulation of chromatin status impinges on genome maintenance and therefore on cancer and aging. As a provocative line of research and based on our preliminary data, we propose that certain chromatin alterations could not only impair but also in some cases promote a more robust response to DNA breaks, which could be a novel and not yet explored way to potentiate the elimination of pre-cancerous cells.
Summary
With the availability of the essentially complete sequence of the human genome, as well as a rapid development of massive sequencing techniques, the research efforts to understand genetics and disease from a cis standpoint will soon reach an endpoint. However, our emerging knowledge of gene regulation networks reveals that epigenetic regulation of the hereditary information plays crucial roles in various biological events through its influence on processes such as transcription, DNA replication and chromosome architecture. Another scenario in which the control of chromatin structure is crucial is the repair of lesions in genomic DNA. There is mounting evidence, particularly from model organisms such as Saccharomyces cerevisiae, that histone modifying enzymes (acetylases, deacetylases, kinases, …) are essential components of the machinery that maintains genome integrity and thereby guards against cancer, degenerative diseases and ageing. However, little is known about the specific “code” of histone tail modifications that coordinate DNA repair, and the impact that an aberrant “histone code” may have on human health. In CHROMOREPAIR we will systematically analyze the chromatin remodelling process that undergoes at DNA lesions and evaluate the impact that chromatin alterations have on the access, signaling and repair of DNA damage. Furthermore, we propose to translate our in vitro knowledge to the development of mouse models that help us evaluate how modulation of chromatin status impinges on genome maintenance and therefore on cancer and aging. As a provocative line of research and based on our preliminary data, we propose that certain chromatin alterations could not only impair but also in some cases promote a more robust response to DNA breaks, which could be a novel and not yet explored way to potentiate the elimination of pre-cancerous cells.
Max ERC Funding
948 426 €
Duration
Start date: 2008-12-01, End date: 2013-11-30
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
Project acronym DECORE
Project Deep Earth Chemistry of the Core
Researcher (PI) James Badro
Host Institution (HI) INSTITUT DE PHYSIQUE DU GLOBE DE PARIS
Call Details Starting Grant (StG), PE8, ERC-2007-StG
Summary Core formation represents the major chemical differentiation event on the terrestrial planets, involving the separation of a metallic liquid from the silicate matrix that subsequently evolves into the current silicate crust and mantle. The generation of the Earth’s magnetic field is ultimately tied to the segregation and crystallization of the core, and is an important factor in establishing planetary habitability. The processes that control core segregation and the depths and temperatures at which this process took place are poorly understood, however. We propose to study those processes. Specifically, the density of the core is lower than would be expected for pure iron, indicating that a light component (O, Si, S, C, H) must be present. Similarly, the Earth’s mantle is richer in iron-loving (“siderophile”) elements, e.g, V, W, Mo, Ru, Pd, etc., than would be expected based upon low pressure metal-silicate partitioning data. Solutions to these problems are hampered by the pressure range of existing experimental data, < 25 GPa, equivalent to ~700 km in the Earth. We propose to extend the accessible range of pressures and temperatures by developing protocols that link the laser-heated diamond anvil cell with analytical techniques such as (i) the NanoSIMS, (ii) the focused ion beam device (FIB), (iii) and transmission and secondary electron microscopy, allowing us to obtain quantitative data on element partitioning and chemical composition at extreme conditions relevant to the Earth’s lower mantle. The technical motivation follows from the fact that the real limitation on trace element partitioning studies at ultra high-pressure has been the grain size of the phases produced at high P-T, relative to the spatial resolution of the analytical methods available to probe the experiments; we can bridge the gap by combining state-of-the-art laser heating experiments with new nano-scale analytical techniques.
Summary
Core formation represents the major chemical differentiation event on the terrestrial planets, involving the separation of a metallic liquid from the silicate matrix that subsequently evolves into the current silicate crust and mantle. The generation of the Earth’s magnetic field is ultimately tied to the segregation and crystallization of the core, and is an important factor in establishing planetary habitability. The processes that control core segregation and the depths and temperatures at which this process took place are poorly understood, however. We propose to study those processes. Specifically, the density of the core is lower than would be expected for pure iron, indicating that a light component (O, Si, S, C, H) must be present. Similarly, the Earth’s mantle is richer in iron-loving (“siderophile”) elements, e.g, V, W, Mo, Ru, Pd, etc., than would be expected based upon low pressure metal-silicate partitioning data. Solutions to these problems are hampered by the pressure range of existing experimental data, < 25 GPa, equivalent to ~700 km in the Earth. We propose to extend the accessible range of pressures and temperatures by developing protocols that link the laser-heated diamond anvil cell with analytical techniques such as (i) the NanoSIMS, (ii) the focused ion beam device (FIB), (iii) and transmission and secondary electron microscopy, allowing us to obtain quantitative data on element partitioning and chemical composition at extreme conditions relevant to the Earth’s lower mantle. The technical motivation follows from the fact that the real limitation on trace element partitioning studies at ultra high-pressure has been the grain size of the phases produced at high P-T, relative to the spatial resolution of the analytical methods available to probe the experiments; we can bridge the gap by combining state-of-the-art laser heating experiments with new nano-scale analytical techniques.
Max ERC Funding
1 509 200 €
Duration
Start date: 2008-11-01, End date: 2013-10-31
Project acronym DEMONS
Project Deciphering Eruptions by Modeling Outputs of Natural Systems
Researcher (PI) Alain Burgisser
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), PE8, ERC-2007-StG
Summary Active volcanoes emit high temperature gases that modify the chemical composition of the Earth’s atmosphere. It is crucial to be able to quantify the contribution of volcanogenic gases to the atmosphere so that the global atmospheric effects of a major eruption can be predicted and so that volcanogenic effects can be discriminated from anthropogenic emissions. At the scale of one volcano, monitoring of gas plumes is a major tool in volcanic risk management. Volcanologists have long measured gas composition and fluxes between and during eruptions and often noted a decoupling between degassing flux and magmatic flux. In parallel, experimental petrologists are now able to calculate the gas composition that is in equilibrium with the magma at depth. However, when the calculated gas composition is compared to that measured at the surface, a general disagreement arises. As a result, it is currently impossible to determine whether a plume is generated in response to passive degassing or to magma ascent. This is a serious drawback as these processes have opposite implications for volcanic activity. Such difficulties are mainly due to the fact that the interplay between degassing mechanisms and gas chemistry has not been addressed. To improve the application of volcanic gas analyses to understanding global geochemical budgets and for the mitigation of volcanic risk, we propose to link deep magmatic processes and surface emissions. Our objective is to model the quantity and composition of volcanic gases as a function of the petrology of the magma at depth and the eruptive regime, and compare those calculations with new measures of plumes at active volcanoes. We will achieve this by modeling the chemical kinetics of degassing in volcanic conduits by using a combination of experimental, field, and numerical approaches. We anticipate building a tool linking flux and composition of gases to eruptive regime, thus opening the door to inverse modeling of volcanic gas observations.
Summary
Active volcanoes emit high temperature gases that modify the chemical composition of the Earth’s atmosphere. It is crucial to be able to quantify the contribution of volcanogenic gases to the atmosphere so that the global atmospheric effects of a major eruption can be predicted and so that volcanogenic effects can be discriminated from anthropogenic emissions. At the scale of one volcano, monitoring of gas plumes is a major tool in volcanic risk management. Volcanologists have long measured gas composition and fluxes between and during eruptions and often noted a decoupling between degassing flux and magmatic flux. In parallel, experimental petrologists are now able to calculate the gas composition that is in equilibrium with the magma at depth. However, when the calculated gas composition is compared to that measured at the surface, a general disagreement arises. As a result, it is currently impossible to determine whether a plume is generated in response to passive degassing or to magma ascent. This is a serious drawback as these processes have opposite implications for volcanic activity. Such difficulties are mainly due to the fact that the interplay between degassing mechanisms and gas chemistry has not been addressed. To improve the application of volcanic gas analyses to understanding global geochemical budgets and for the mitigation of volcanic risk, we propose to link deep magmatic processes and surface emissions. Our objective is to model the quantity and composition of volcanic gases as a function of the petrology of the magma at depth and the eruptive regime, and compare those calculations with new measures of plumes at active volcanoes. We will achieve this by modeling the chemical kinetics of degassing in volcanic conduits by using a combination of experimental, field, and numerical approaches. We anticipate building a tool linking flux and composition of gases to eruptive regime, thus opening the door to inverse modeling of volcanic gas observations.
Max ERC Funding
1 364 478 €
Duration
Start date: 2008-09-01, End date: 2012-12-31
