Project acronym LVFM
Project Learning and volatility in financial markets: theory, experiments and empirics
Researcher (PI) Antonio Guarino
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), SH1, ERC-2007-StG
Summary The project aims to study learning and volatility in financial markets. We will develop a theoretical market microstructure model to analyze how informational inefficiencies can arise in financial markets even though traders (who have non speculative reasons to trade) are allowed to buy or sell any quantity of an asset (in a continuous action space). In this theoretical framework, we will also analyze the case in which the asset value can change over time (e.g., because of shocks to the economy). We will study how learning occurs in this economy with changing fundamentals and how learning affects price volatility. This will create a bridge between the theoretical literature on learning and the empirical literature on time varying volatility (e.g., ARCH and GARCH). After developing the theoretical analyses, we will test the predictions in experiments, and proceed to a structural estimation of our models. We will run both field and laboratory experiments. The structural estimation will use transaction data in order to shed light on the process of information aggregation and volatility in different markets (e.g., more or less speculative) and different conditions (tranquil times versus financial crises).
Summary
The project aims to study learning and volatility in financial markets. We will develop a theoretical market microstructure model to analyze how informational inefficiencies can arise in financial markets even though traders (who have non speculative reasons to trade) are allowed to buy or sell any quantity of an asset (in a continuous action space). In this theoretical framework, we will also analyze the case in which the asset value can change over time (e.g., because of shocks to the economy). We will study how learning occurs in this economy with changing fundamentals and how learning affects price volatility. This will create a bridge between the theoretical literature on learning and the empirical literature on time varying volatility (e.g., ARCH and GARCH). After developing the theoretical analyses, we will test the predictions in experiments, and proceed to a structural estimation of our models. We will run both field and laboratory experiments. The structural estimation will use transaction data in order to shed light on the process of information aggregation and volatility in different markets (e.g., more or less speculative) and different conditions (tranquil times versus financial crises).
Max ERC Funding
765 000 €
Duration
Start date: 2008-10-01, End date: 2014-09-30
Project acronym MADEM
Project Market Design and the Evolution of Markets
Researcher (PI) Estelle Cantillon
Host Institution (HI) UNIVERSITE LIBRE DE BRUXELLES
Call Details Starting Grant (StG), SH1, ERC-2007-StG
Summary The broad aim of this research program is to understand how markets get created, how they evolve, and how specific market organizations affect economic outcomes. It combines theoretical and empirical analyses of specific markets and includes the development of new methods to map theory to data and vice versa. Each market provides a concrete ground to explore the broad questions the project addresses and motivates a distinct set of questions. The first class of markets the research will consider are financial markets. These can be viewed as the archetype of large markets where prices play the main role in the allocation. The focus there will on market creation, market evolution and the process of competition. The second class of markets the research will consider are allocation mechanisms where prices do not play a role in the allocation, making efficiency hard to obtain. The focus there will be on strategic manipulation of preferences by participants, their consequences on outcomes and possible remedies. Together, these markets will contribute to our understanding of how market rules affect outcomes and performance, to what extent laissez-faire evolution fosters efficient market organizations, and when and how public intervention can help generate better market organizations.
Summary
The broad aim of this research program is to understand how markets get created, how they evolve, and how specific market organizations affect economic outcomes. It combines theoretical and empirical analyses of specific markets and includes the development of new methods to map theory to data and vice versa. Each market provides a concrete ground to explore the broad questions the project addresses and motivates a distinct set of questions. The first class of markets the research will consider are financial markets. These can be viewed as the archetype of large markets where prices play the main role in the allocation. The focus there will on market creation, market evolution and the process of competition. The second class of markets the research will consider are allocation mechanisms where prices do not play a role in the allocation, making efficiency hard to obtain. The focus there will be on strategic manipulation of preferences by participants, their consequences on outcomes and possible remedies. Together, these markets will contribute to our understanding of how market rules affect outcomes and performance, to what extent laissez-faire evolution fosters efficient market organizations, and when and how public intervention can help generate better market organizations.
Max ERC Funding
840 000 €
Duration
Start date: 2008-09-01, End date: 2014-02-28
Project acronym MAMMALIANDEVELOPMENT
Project A systems-level understanding of the novel principle in early mammalian development
Researcher (PI) Takashi Hiiragi
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Early mammalian development is a unique process creating an extraembryonic structure. Despite its importance for understanding mammalian development and direct relevance to clinical practice, the mechanism underlying polarity establishment in the mammalian embryo has long been elusive. One of the major obstacles is the lack of description in molecular terms, since very few genes are known to specify the early lineages. Our recent studies provide a conceptual basis, suggesting that the mechanism is unique to mammals. The primary aim of this proposal is to elucidate the molecular program and the novel principle of early mammalian development at a systems level. To comprehensively identify molecules involved in early mouse development, we will conduct two complementary screens. One is a lentivirus-based promoter-trap screen: Venus-reporter is to be expressed under the endogenous control of the integrated genomic locus, which will be monitored using our live-embryo imaging system. Embryos showing a differential expression pattern will be selected for further analysis. As a complementary approach, single-blastomere-derived cRNAs are generated from embryos of various stages by the recently developed single-cell cRNA amplification method, followed by microarray analysis to statistically identify gene clusters differentially expressed in specific blastomeres. Function of the genes identified in two screens will be examined by RNAi and maternally conditional KO. Finally, the knowledge will be integrated into our computer simulation that successfully reconstitutes blastocyst morphogenesis. In the long term, the obtained tools (markers and Venus-trap lines) will provide a basis for functional siRNA screen. Genetic screen in early mouse embryos has never been achieved. Though we anticipate certain difficulties, we are confident that with the relevant expertise of collaborators and ourselves, these can be resolved and a substantial advance will be made in this important area.
Summary
Early mammalian development is a unique process creating an extraembryonic structure. Despite its importance for understanding mammalian development and direct relevance to clinical practice, the mechanism underlying polarity establishment in the mammalian embryo has long been elusive. One of the major obstacles is the lack of description in molecular terms, since very few genes are known to specify the early lineages. Our recent studies provide a conceptual basis, suggesting that the mechanism is unique to mammals. The primary aim of this proposal is to elucidate the molecular program and the novel principle of early mammalian development at a systems level. To comprehensively identify molecules involved in early mouse development, we will conduct two complementary screens. One is a lentivirus-based promoter-trap screen: Venus-reporter is to be expressed under the endogenous control of the integrated genomic locus, which will be monitored using our live-embryo imaging system. Embryos showing a differential expression pattern will be selected for further analysis. As a complementary approach, single-blastomere-derived cRNAs are generated from embryos of various stages by the recently developed single-cell cRNA amplification method, followed by microarray analysis to statistically identify gene clusters differentially expressed in specific blastomeres. Function of the genes identified in two screens will be examined by RNAi and maternally conditional KO. Finally, the knowledge will be integrated into our computer simulation that successfully reconstitutes blastocyst morphogenesis. In the long term, the obtained tools (markers and Venus-trap lines) will provide a basis for functional siRNA screen. Genetic screen in early mouse embryos has never been achieved. Though we anticipate certain difficulties, we are confident that with the relevant expertise of collaborators and ourselves, these can be resolved and a substantial advance will be made in this important area.
Max ERC Funding
1 150 000 €
Duration
Start date: 2008-07-01, End date: 2013-12-31
Project acronym MECHANOSENSATION
Project What is the molecular mechanism of mechanosensation? Mechanosensitive channel of large conductance, MscL, as a model
Researcher (PI) Armagan Kocer
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Call Details Starting Grant (StG), LS7, ERC-2007-StG
Summary “Equipped with his five senses, man explores the universe around him and calls the adventure science” E.P. Hubble It is amazing how much we have learned about the working of our universe by using our five senses and how little we still know about the working of these senses themselves! Even though the molecular mechanism of sight, taste, and smell is known, we still don’t know how the mechanical sensations of touch and hearing function at the molecular level. Mechanosensitive (MS) ion channels, present in membranes, are the molecules that sense membrane tension in all species ranging from bacteria to man. They stay functional even in artificial membranes, indicating that mechanosensation occurs at the protein-lipid interface. In an effort to understand the mechanism of force sensation, the major limitation has been the inability to ‘observe’ the molecular changes occurring in MS channels from the onset of the force. The aim of this proposal is to understand how channel proteins sense mechanical force at the molecular level. A bacterial channel, MscL, will be used as a model for its natural function to couple tension in the membrane to protein conformational changes. Here, on the basis of my recent findings, I propose to build on synthetic biology approaches to develop unique tools to specifically address the MS channel, allowing controlling its activity extrinsically and reversibly. In combination with the spectroscopic techniques, I want to elucidate the mechanism of mechanosensation in MscL by measuring structural changes in the protein and its interaction with the surrounding lipids, starting from the onset of the force. The research will clarify not only the long-standing question of how MscL senses tension, but it will also shed light on the common property of mechanosensitivity among nature’s sensors in higher organisms; transient receptor-potential (TRP) channels, which are involved in hearing, touching and other sensory actions.
Summary
“Equipped with his five senses, man explores the universe around him and calls the adventure science” E.P. Hubble It is amazing how much we have learned about the working of our universe by using our five senses and how little we still know about the working of these senses themselves! Even though the molecular mechanism of sight, taste, and smell is known, we still don’t know how the mechanical sensations of touch and hearing function at the molecular level. Mechanosensitive (MS) ion channels, present in membranes, are the molecules that sense membrane tension in all species ranging from bacteria to man. They stay functional even in artificial membranes, indicating that mechanosensation occurs at the protein-lipid interface. In an effort to understand the mechanism of force sensation, the major limitation has been the inability to ‘observe’ the molecular changes occurring in MS channels from the onset of the force. The aim of this proposal is to understand how channel proteins sense mechanical force at the molecular level. A bacterial channel, MscL, will be used as a model for its natural function to couple tension in the membrane to protein conformational changes. Here, on the basis of my recent findings, I propose to build on synthetic biology approaches to develop unique tools to specifically address the MS channel, allowing controlling its activity extrinsically and reversibly. In combination with the spectroscopic techniques, I want to elucidate the mechanism of mechanosensation in MscL by measuring structural changes in the protein and its interaction with the surrounding lipids, starting from the onset of the force. The research will clarify not only the long-standing question of how MscL senses tension, but it will also shed light on the common property of mechanosensitivity among nature’s sensors in higher organisms; transient receptor-potential (TRP) channels, which are involved in hearing, touching and other sensory actions.
Max ERC Funding
1 449 236 €
Duration
Start date: 2008-09-01, End date: 2014-02-28
Project acronym MEDIA AND POLICY
Project The impact of mass media on public policy
Researcher (PI) David Strömberg
Host Institution (HI) STOCKHOLMS UNIVERSITET
Call Details Starting Grant (StG), SH1, ERC-2007-StG
Summary This project will study political economics issues, that is, how public policies are influenced by political considerations. The emphasis is on the mass media's role in shaping government policies. A smaller part will also analyze how different political institutions and economic outcomes influence policy and the impact of extreme weather events. The project will mainly be empirical, using statistical methods with a focus on identifying causal effects, rather than correlations. The study of media effects will analyze the political impact of having a press actively covering politics. This is an important issue, largely unanswered because the presence of an active press is endogenous to things like corruption and voter information. We will address this question in the special case of media coverage of US Congressional elections. To identify the effect of news, we will use the fact that the amount of coverage is driven to a large extent by the coincidental match between media markets and congressional districts. We intend to analyze the effect of active press coverage on, (i) voter information, (ii) politicians actions, and (iii) federal funds per capita. The project will also investigate how political institutions and economic outcomes influences the health impacts (such as mortality among old and infants) of weather extremes. Historical weather data at a very detailed geographical level will be combined with socio-economic data in a panel (longitudinal) form. This is joint work with meteorologists who will construct historical weather data at fine grids across the globe. The part dealing with structural political economics aims to develop a framework for investigating the effects of institutions on economic policy. In existing work, there is a disconnect between the theoretical modelling and empirical applications. The aim is to close this gap.
Summary
This project will study political economics issues, that is, how public policies are influenced by political considerations. The emphasis is on the mass media's role in shaping government policies. A smaller part will also analyze how different political institutions and economic outcomes influence policy and the impact of extreme weather events. The project will mainly be empirical, using statistical methods with a focus on identifying causal effects, rather than correlations. The study of media effects will analyze the political impact of having a press actively covering politics. This is an important issue, largely unanswered because the presence of an active press is endogenous to things like corruption and voter information. We will address this question in the special case of media coverage of US Congressional elections. To identify the effect of news, we will use the fact that the amount of coverage is driven to a large extent by the coincidental match between media markets and congressional districts. We intend to analyze the effect of active press coverage on, (i) voter information, (ii) politicians actions, and (iii) federal funds per capita. The project will also investigate how political institutions and economic outcomes influences the health impacts (such as mortality among old and infants) of weather extremes. Historical weather data at a very detailed geographical level will be combined with socio-economic data in a panel (longitudinal) form. This is joint work with meteorologists who will construct historical weather data at fine grids across the globe. The part dealing with structural political economics aims to develop a framework for investigating the effects of institutions on economic policy. In existing work, there is a disconnect between the theoretical modelling and empirical applications. The aim is to close this gap.
Max ERC Funding
799 945 €
Duration
Start date: 2008-09-01, End date: 2014-08-31
Project acronym MICROFLEX
Project Microbiology of Dehalococcoides-like Chloroflexi
Researcher (PI) Lorenz Adrian
Host Institution (HI) HELMHOLTZ-ZENTRUM FUR UMWELTFORSCHUNG GMBH - UFZ
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary I propose to initiate research on a specific group of bacteria, here denominated as the “Dehalococcoides-like Chloroflexi”. This group of bacteria is formed by several cultivated strains of the genus Dehalococcoides and many sequences of uncultivated organisms mostly from marine sediment or subsurface locations. All together form one subphylum of the Chloroflexi. Bacteria of the Dehalococcoides-like Chloroflexi are of particular importance for two independent reasons: first, the subphylum contains all bacteria known to transform under anaerobic conditions toxic and persistent halogenated compounds such as chlorinated dioxins, benzenes, biphenyls, vinyl chloride or brominated biphenylethers; secondly, massive amounts of Dehalococcoides-like Chloroflexi have recently been detected in marine organic-rich deep sediments dominating the populations with up to 80% of the total cell counts. However, many aspects of the physiology of Dehalococcoides species are unclear and almost nothing is known about Chloroflexi in deep sediments. I have worked for many years on the microbiology, biochemistry and genomics of Dehalococcoides species. With the proposed group I plan to focus on the physiological links between Chloroflexi in contaminated aquifers and those in marine sediments. Initially, cultures of marine sediment-Chloroflexi will be established in our lab and compared with pure Dehalococcoides strains. Objectives of our research towards marine Chloroflexi will be the description of the physiology, of the biochemistry of energy conservation and of key genes encoded in the genomes. It is anticipated that the research leads to a substantiated hypothesis on the mode of energy fixation in marine deep-sediments and an initial description of the role of Dehalococcoides-like Chloroflexi in biogeochemical cycles. We also expect to find insights into Chloroflexi evolution and their role in earth history by comparing genomes between Dehalococcoides species and marine Chloroflexi.
Summary
I propose to initiate research on a specific group of bacteria, here denominated as the “Dehalococcoides-like Chloroflexi”. This group of bacteria is formed by several cultivated strains of the genus Dehalococcoides and many sequences of uncultivated organisms mostly from marine sediment or subsurface locations. All together form one subphylum of the Chloroflexi. Bacteria of the Dehalococcoides-like Chloroflexi are of particular importance for two independent reasons: first, the subphylum contains all bacteria known to transform under anaerobic conditions toxic and persistent halogenated compounds such as chlorinated dioxins, benzenes, biphenyls, vinyl chloride or brominated biphenylethers; secondly, massive amounts of Dehalococcoides-like Chloroflexi have recently been detected in marine organic-rich deep sediments dominating the populations with up to 80% of the total cell counts. However, many aspects of the physiology of Dehalococcoides species are unclear and almost nothing is known about Chloroflexi in deep sediments. I have worked for many years on the microbiology, biochemistry and genomics of Dehalococcoides species. With the proposed group I plan to focus on the physiological links between Chloroflexi in contaminated aquifers and those in marine sediments. Initially, cultures of marine sediment-Chloroflexi will be established in our lab and compared with pure Dehalococcoides strains. Objectives of our research towards marine Chloroflexi will be the description of the physiology, of the biochemistry of energy conservation and of key genes encoded in the genomes. It is anticipated that the research leads to a substantiated hypothesis on the mode of energy fixation in marine deep-sediments and an initial description of the role of Dehalococcoides-like Chloroflexi in biogeochemical cycles. We also expect to find insights into Chloroflexi evolution and their role in earth history by comparing genomes between Dehalococcoides species and marine Chloroflexi.
Max ERC Funding
1 287 258 €
Duration
Start date: 2008-06-01, End date: 2013-12-31
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
Project acronym MIGRANT SOCIALITIES
Project New Migrant Socialities: Ethnic Club Cultures in Urban Europe
Researcher (PI) Kira Kosnick
Host Institution (HI) JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN
Call Details Starting Grant (StG), SH2, ERC-2007-StG
Summary The project investigates new forms of sociality that young people with migrant background are producing in the context of urban club cultures in three European cities. It comparatively studies the phenomenon of ethnic club scenes with Turkish, South Asian and Maghrebi orientations in Berlin, London and Paris, corresponding to the major immigrant groups in each city and country. The project aims to explore how migrants participate in forms of social engagement and cultural experimentation that are specific to metropolitan city life, but have so far been not been addressed as relevant to the lives of ethnic minorities. Research seeks to shift attention from the predominant research focus on migrant identity to a focus on migrant practices of sociality, countering the heavy bias towards the study of attitudes and cultural identifications that tends to dominate across different disciplines. Its novel approach combines a focus on socio-cultural practices with an interest in urban scenes as fluid social formations that are semi-public and lack defined membership or criteria of belonging. Through ethnographic case studies carried out with a team of researchers in and across the three cities, the project explores the potential of urban club scenes for producing and experiencing different kinds of solidarity and encounter among disadvantaged groups.
Summary
The project investigates new forms of sociality that young people with migrant background are producing in the context of urban club cultures in three European cities. It comparatively studies the phenomenon of ethnic club scenes with Turkish, South Asian and Maghrebi orientations in Berlin, London and Paris, corresponding to the major immigrant groups in each city and country. The project aims to explore how migrants participate in forms of social engagement and cultural experimentation that are specific to metropolitan city life, but have so far been not been addressed as relevant to the lives of ethnic minorities. Research seeks to shift attention from the predominant research focus on migrant identity to a focus on migrant practices of sociality, countering the heavy bias towards the study of attitudes and cultural identifications that tends to dominate across different disciplines. Its novel approach combines a focus on socio-cultural practices with an interest in urban scenes as fluid social formations that are semi-public and lack defined membership or criteria of belonging. Through ethnographic case studies carried out with a team of researchers in and across the three cities, the project explores the potential of urban club scenes for producing and experiencing different kinds of solidarity and encounter among disadvantaged groups.
Max ERC Funding
1 244 518 €
Duration
Start date: 2009-04-01, End date: 2013-03-31
Project acronym MIREG
Project Identifying novel regulatory mechanisms of miRNA functions
Researcher (PI) Reuven Agami
Host Institution (HI) STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary microRNAs (miRNAs) are master regulators of gene expression capable of defining and altering cell identity. Because of their potency, small size, simple mode of action (target recognition through a Watson-Crick type of base pairing) and the possibility to inhibit them in vivo, miRNAs are valuable therapeutic targets. Recently, we have used novel functional-genetic screening approaches and identified the miR-372, 373 and 520, as well as the miR-221&222 family as cancerous miRNAs. These miRNAs are oncogenes, as they are deregulated in specific types of cancers, target tumor suppressors and their inhibition reverts cancerous phenotypes. However, at present almost nothing is known about the mechanisms governing the expression and function of these, as well as many other, oncogenic miRNAs. Here, I propose experiments to identify and characterize factors affecting the activity of oncogenic miRNAs using an array of molecular and genetic tools. Our preliminary results indicate the existence of novel regulators and mechanisms of miRNA activity. We therefore believe that the information collected here not only will lead to a better understanding of miRNA functions, but will also identify novel modes of manipulating miRNA activity in human disease.
Summary
microRNAs (miRNAs) are master regulators of gene expression capable of defining and altering cell identity. Because of their potency, small size, simple mode of action (target recognition through a Watson-Crick type of base pairing) and the possibility to inhibit them in vivo, miRNAs are valuable therapeutic targets. Recently, we have used novel functional-genetic screening approaches and identified the miR-372, 373 and 520, as well as the miR-221&222 family as cancerous miRNAs. These miRNAs are oncogenes, as they are deregulated in specific types of cancers, target tumor suppressors and their inhibition reverts cancerous phenotypes. However, at present almost nothing is known about the mechanisms governing the expression and function of these, as well as many other, oncogenic miRNAs. Here, I propose experiments to identify and characterize factors affecting the activity of oncogenic miRNAs using an array of molecular and genetic tools. Our preliminary results indicate the existence of novel regulators and mechanisms of miRNA activity. We therefore believe that the information collected here not only will lead to a better understanding of miRNA functions, but will also identify novel modes of manipulating miRNA activity in human disease.
Max ERC Funding
1 349 760 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym MOLINFLAM
Project Molecular dissection of inflammatory pathways
Researcher (PI) Attila Mocsai
Host Institution (HI) SEMMELWEIS EGYETEM
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary Inflammatory diseases are highly prevalent, often chronic diseases that cause diminished quality of life and are connected with major causes of death in Western societies. Despite their societal impact, their pathomechanism is incompletely understood, hindering development of novel therapeutic strategies. In particular, little is known about the intracellular signal transduction processes involved in the tissue destruction phase of aggressive autoimmune diseases such as rheumatoid arthritis. The present proposal aims to clarify this issue using in vivo and in vitro studies on genetically manipulated mice. During the proposed studies, mice deficient in various signal transduction molecules such as Syk, PLCg2, Gab2 and p190 RhoGAPs will be used to test their contribution to inflammatory responses. In vitro studies will test the activation of major effector cells of inflammation (neutrophils, macrophages and osteoclasts) while in vivo studies will utilize mouse models such as autoantibody- and cytokine-induced inflammatory arthritis or autoantibody-induced glomerulonephritis. Further studies will be performed to test the contribution of the above signaling molecules to disease pathogenesis in a lineage-restricted manner, using the Cre-lox approach. Finally, wild type and mutant versions of the signaling molecules tested will be retrovirally re-expressed into the relevant knockout hematopoietic stem cells in vivo to allow structure-function studies during in vivo inflammation. Two novel transgenic strains and a knock-in (floxed) mutant will also be generated during the course of the project. Using state-of-the-art approaches and techniques, this project will provide information at unprecedented molecular detail on signal transduction mechanisms involved in inflammatory diseases, and is expected to point to possible future targets of novel anti-inflammatory therapies.
Summary
Inflammatory diseases are highly prevalent, often chronic diseases that cause diminished quality of life and are connected with major causes of death in Western societies. Despite their societal impact, their pathomechanism is incompletely understood, hindering development of novel therapeutic strategies. In particular, little is known about the intracellular signal transduction processes involved in the tissue destruction phase of aggressive autoimmune diseases such as rheumatoid arthritis. The present proposal aims to clarify this issue using in vivo and in vitro studies on genetically manipulated mice. During the proposed studies, mice deficient in various signal transduction molecules such as Syk, PLCg2, Gab2 and p190 RhoGAPs will be used to test their contribution to inflammatory responses. In vitro studies will test the activation of major effector cells of inflammation (neutrophils, macrophages and osteoclasts) while in vivo studies will utilize mouse models such as autoantibody- and cytokine-induced inflammatory arthritis or autoantibody-induced glomerulonephritis. Further studies will be performed to test the contribution of the above signaling molecules to disease pathogenesis in a lineage-restricted manner, using the Cre-lox approach. Finally, wild type and mutant versions of the signaling molecules tested will be retrovirally re-expressed into the relevant knockout hematopoietic stem cells in vivo to allow structure-function studies during in vivo inflammation. Two novel transgenic strains and a knock-in (floxed) mutant will also be generated during the course of the project. Using state-of-the-art approaches and techniques, this project will provide information at unprecedented molecular detail on signal transduction mechanisms involved in inflammatory diseases, and is expected to point to possible future targets of novel anti-inflammatory therapies.
Max ERC Funding
1 200 000 €
Duration
Start date: 2008-10-01, End date: 2014-03-31
