Project acronym ALK7
Project Metabolic control by the TGF-² superfamily receptor ALK7: A novel regulator of insulin secretion, fat accumulation and energy balance
Researcher (PI) Carlos Ibanez
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary The aim of this proposal is to understand a novel regulatory signaling network controlling insulin secretion, fat accumulation and energy balance centered around selected components of the TGF-² signaling system, including Activins A and B, GDF-3 and their receptors ALK7 and ALK4. Recent results from my laboratory indicate that these molecules are part of paracrine signaling networks that control important functions in pancreatic islets and adipose tissue through feedback inhibition and feed-forward regulation. These discoveries have open up a new research area with important implications for the understanding of metabolic networks and the treatment of human metabolic syndromes, such as diabetes and obesity.
To drive progress in this new research area beyond the state-of-the-art it is proposed to: i) Elucidate the molecular mechanisms by which Activins regulate Ca2+ influx and insulin secretion in pancreatic ²-cells; ii) Elucidate the molecular mechanisms underlying the effects of GDF-3 on adipocyte metabolism, turnover and fat accumulation; iii) Investigate the interplay between insulin levels and fat deposition in the development of insulin resistance using mutant mice lacking Activin B and GDF-3; iv) Investigate tissue-specific contributions of ALK7 and ALK4 signaling to metabolic control by generating and characterizing conditional mutant mice; v) Investigate the effects of specific and reversible inactivation of ALK7 and ALK4 on metabolic regulation using a novel chemical-genetic approach based on analog-sensitive alleles.
This is research of a high-gain/high-risk nature. It is posed to open unique opportunities for further exploration of complex metabolic networks. The development of drugs capable of enhancing insulin secretion, limiting fat accumulation and ameliorating diet-induced obesity by targeting components of the ALK7 signaling network will find a strong rationale in the results of the proposed work.
Summary
The aim of this proposal is to understand a novel regulatory signaling network controlling insulin secretion, fat accumulation and energy balance centered around selected components of the TGF-² signaling system, including Activins A and B, GDF-3 and their receptors ALK7 and ALK4. Recent results from my laboratory indicate that these molecules are part of paracrine signaling networks that control important functions in pancreatic islets and adipose tissue through feedback inhibition and feed-forward regulation. These discoveries have open up a new research area with important implications for the understanding of metabolic networks and the treatment of human metabolic syndromes, such as diabetes and obesity.
To drive progress in this new research area beyond the state-of-the-art it is proposed to: i) Elucidate the molecular mechanisms by which Activins regulate Ca2+ influx and insulin secretion in pancreatic ²-cells; ii) Elucidate the molecular mechanisms underlying the effects of GDF-3 on adipocyte metabolism, turnover and fat accumulation; iii) Investigate the interplay between insulin levels and fat deposition in the development of insulin resistance using mutant mice lacking Activin B and GDF-3; iv) Investigate tissue-specific contributions of ALK7 and ALK4 signaling to metabolic control by generating and characterizing conditional mutant mice; v) Investigate the effects of specific and reversible inactivation of ALK7 and ALK4 on metabolic regulation using a novel chemical-genetic approach based on analog-sensitive alleles.
This is research of a high-gain/high-risk nature. It is posed to open unique opportunities for further exploration of complex metabolic networks. The development of drugs capable of enhancing insulin secretion, limiting fat accumulation and ameliorating diet-induced obesity by targeting components of the ALK7 signaling network will find a strong rationale in the results of the proposed work.
Max ERC Funding
2 462 154 €
Duration
Start date: 2009-04-01, End date: 2014-03-31
Project acronym ANGIOMIRS
Project microRNAs in vascular homeostasis
Researcher (PI) Stefanie Dimmeler
Host Institution (HI) JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Despite improved therapy, cardiovascular diseases remain the most prevalent diseases in the European Union and the incidence is rising due to increased obesity and ageing. The fine-tuned regulation of vascular functions is essential not only for preventing atherosclerotic diseases, but also after tissue injury, where the coordinated growth and maturation of new blood vessels provides oxygen and nutrient supply. On the other hand, excessive vessel growth or the generation of immature, leaky vessels contributes to pathological angiogenesis. Thus, the regulation of the complex processes governing vessel growth and maturation has broad impacts for several diseases ranging from tumor angiogenesis, diabetic retinopathy, to ischemic cardiovascular diseases. MicroRNAs (miRs) are small noncoding RNAs, which play a crucial role in embryonic development and tissue homeostasis. However, only limited information is available regarding the role of miRs in the vasculature. MiRs regulate gene expression by binding to the target mRNA leading either to degradation or to translational repression. Because miRs control patterns of target genes, miRs represent an attractive and promising therapeutic target to interfere with complex processes such as neovascularization and repair of ischemic tissues. Therefore, the present application aims to identify miRs in the vasculature, which regulate vessel growth and vessel remodelling and may, thus, serve as therapeutic targets in ischemic diseases. Since ageing critically impairs endothelial function, neovascularization and vascular repair, we will specifically identify miRs, which are dysregulated during ageing in endothelial cells and pro-angiogenic progenitor cells, in order to develop novel strategies to rescue age-induced impairment of neovascularization. Beyond the specific scope of the present application, the principle findings may have impact for other diseases, where deregulated vessel growth causes or accelerates disease states.
Summary
Despite improved therapy, cardiovascular diseases remain the most prevalent diseases in the European Union and the incidence is rising due to increased obesity and ageing. The fine-tuned regulation of vascular functions is essential not only for preventing atherosclerotic diseases, but also after tissue injury, where the coordinated growth and maturation of new blood vessels provides oxygen and nutrient supply. On the other hand, excessive vessel growth or the generation of immature, leaky vessels contributes to pathological angiogenesis. Thus, the regulation of the complex processes governing vessel growth and maturation has broad impacts for several diseases ranging from tumor angiogenesis, diabetic retinopathy, to ischemic cardiovascular diseases. MicroRNAs (miRs) are small noncoding RNAs, which play a crucial role in embryonic development and tissue homeostasis. However, only limited information is available regarding the role of miRs in the vasculature. MiRs regulate gene expression by binding to the target mRNA leading either to degradation or to translational repression. Because miRs control patterns of target genes, miRs represent an attractive and promising therapeutic target to interfere with complex processes such as neovascularization and repair of ischemic tissues. Therefore, the present application aims to identify miRs in the vasculature, which regulate vessel growth and vessel remodelling and may, thus, serve as therapeutic targets in ischemic diseases. Since ageing critically impairs endothelial function, neovascularization and vascular repair, we will specifically identify miRs, which are dysregulated during ageing in endothelial cells and pro-angiogenic progenitor cells, in order to develop novel strategies to rescue age-induced impairment of neovascularization. Beyond the specific scope of the present application, the principle findings may have impact for other diseases, where deregulated vessel growth causes or accelerates disease states.
Max ERC Funding
2 375 394 €
Duration
Start date: 2009-03-01, End date: 2014-02-28
Project acronym AP-1-FUN
Project AP-1 (Fos/Jun) Functions in Physiology and Disease
Researcher (PI) Erwin F. Wagner
Host Institution (HI) FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Our research interests lie in breaking new ground in studying mechanism-based functions of AP-1 (Fos/Jun) in vivo with the aim of obtaining a more global perspective on AP-1 in human physiology and disease/cancer. The unresolved issues regarding the AP-1 subunit composition will be tackled biochemically and genetically in various cell types including bone, liver and skin, the primary organs affected by altered AP-1 activity. I plan to utilize the knowledge gained on AP-1 functions in the mouse and transfer it to human disease. The opportunities here lie in exploiting the knowledge of AP-1 target genes and utilizing this information to interfere with pathways involved in normal physiology and disease/cancer. The past investigations revealed that the functions of AP-1 are an essential node at the crossroads between life and death in different cellular systems. I plan to further exploit our findings and concentrate on utilising better mouse models to define these connections. The emphasis will be on identifying molecular signatures and potential treatments in models for cancer, inflammatory and fibrotic diseases. Exploring genetically modified stem cell-based therapies in murine and human cells is an ongoing challenge I would like to meet in the forthcoming years at the CNIO. In addition, the mouse models will be used for mechanism-driven therapeutic strategies and these studies will be undertaken in collaboration with the Experimental Therapeutics Division and the service units such as the tumor bank. The project proposal is divided into 6 Goals (see also Figure 1): Some are a logical continuation based on previous work with completely new aspects (Goal 1-2), some focussing on in depth molecular analyses of disease models with innovative and unconventional concepts, such as for inflammation and cancer, psoriasis and fibrosis (Goal 3-5). A final section is devoted to mouse and human ES cells and their impact for regenerative medicine in bone diseases and cancer.
Summary
Our research interests lie in breaking new ground in studying mechanism-based functions of AP-1 (Fos/Jun) in vivo with the aim of obtaining a more global perspective on AP-1 in human physiology and disease/cancer. The unresolved issues regarding the AP-1 subunit composition will be tackled biochemically and genetically in various cell types including bone, liver and skin, the primary organs affected by altered AP-1 activity. I plan to utilize the knowledge gained on AP-1 functions in the mouse and transfer it to human disease. The opportunities here lie in exploiting the knowledge of AP-1 target genes and utilizing this information to interfere with pathways involved in normal physiology and disease/cancer. The past investigations revealed that the functions of AP-1 are an essential node at the crossroads between life and death in different cellular systems. I plan to further exploit our findings and concentrate on utilising better mouse models to define these connections. The emphasis will be on identifying molecular signatures and potential treatments in models for cancer, inflammatory and fibrotic diseases. Exploring genetically modified stem cell-based therapies in murine and human cells is an ongoing challenge I would like to meet in the forthcoming years at the CNIO. In addition, the mouse models will be used for mechanism-driven therapeutic strategies and these studies will be undertaken in collaboration with the Experimental Therapeutics Division and the service units such as the tumor bank. The project proposal is divided into 6 Goals (see also Figure 1): Some are a logical continuation based on previous work with completely new aspects (Goal 1-2), some focussing on in depth molecular analyses of disease models with innovative and unconventional concepts, such as for inflammation and cancer, psoriasis and fibrosis (Goal 3-5). A final section is devoted to mouse and human ES cells and their impact for regenerative medicine in bone diseases and cancer.
Max ERC Funding
2 500 000 €
Duration
Start date: 2009-11-01, End date: 2015-10-31
Project acronym CADRE
Project Cardiac Death and Regeneration
Researcher (PI) Michael David Schneider
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Cardiac muscle death, unmatched by muscle cell creation, is the hallmark of acute myocardial infarction and chronic cardiomyopathies. The notion of heart failure as a muscle-cell deficiency disease has driven interest worldwide in ways to increase heart muscle cell number, by over-riding cell cycle constraints, suppressing cell death, or, most directly, cell grafting. Using stem cell antigen-1, we previously identified telomerase-expressing cells in adult mouse myocardium, which have salutary properties for bona fide cardiac regeneration. Here, we seek to address systematically the mechanisms for long-term self-renewal in Sca-1+ adult cardiac progenitor cells and in the smaller side population fraction, which is clonogenic and expresses telomerase at even higher levels. Specifically, we propose to study the roles of telomerase and of the telomere-capping protein, TRF2. Aim 1, Determine the properties of adult cardiac progenitor cells in mice that lack the RNA component of telomerase (TERC). Aim 2, Determine the properties of adult cardiac progenitor cells in mice that lack the catalytic component (TERT). To distinguish between effects of these two gene products themselves versus those that depend on cumulative telomere dysfunction, G2- and G5-null mice will be compared. Aim 3, Determine the properties of adult cardiac muscle and adult cardiac progenitor cells that lack the telomere-capping protein TRF2. Aim 4, Test the prediction that forced expression of TERT and TRF2 can augment cardiac muscle engraftment in vivo and enhance the clonal derivation of adult cardiac progenitor cells in vitro, without adversely affecting the cells differentiation potential. Work proposed in Aims 1-3 would provide indispensable fundamental information about the function of endogenous telomerase in adult cardiac progenitor cells. Conversely, work in Aim 4 would test potential therapeutic implications of telomerase and a telomere-capping protein with this auspicious population.
Summary
Cardiac muscle death, unmatched by muscle cell creation, is the hallmark of acute myocardial infarction and chronic cardiomyopathies. The notion of heart failure as a muscle-cell deficiency disease has driven interest worldwide in ways to increase heart muscle cell number, by over-riding cell cycle constraints, suppressing cell death, or, most directly, cell grafting. Using stem cell antigen-1, we previously identified telomerase-expressing cells in adult mouse myocardium, which have salutary properties for bona fide cardiac regeneration. Here, we seek to address systematically the mechanisms for long-term self-renewal in Sca-1+ adult cardiac progenitor cells and in the smaller side population fraction, which is clonogenic and expresses telomerase at even higher levels. Specifically, we propose to study the roles of telomerase and of the telomere-capping protein, TRF2. Aim 1, Determine the properties of adult cardiac progenitor cells in mice that lack the RNA component of telomerase (TERC). Aim 2, Determine the properties of adult cardiac progenitor cells in mice that lack the catalytic component (TERT). To distinguish between effects of these two gene products themselves versus those that depend on cumulative telomere dysfunction, G2- and G5-null mice will be compared. Aim 3, Determine the properties of adult cardiac muscle and adult cardiac progenitor cells that lack the telomere-capping protein TRF2. Aim 4, Test the prediction that forced expression of TERT and TRF2 can augment cardiac muscle engraftment in vivo and enhance the clonal derivation of adult cardiac progenitor cells in vitro, without adversely affecting the cells differentiation potential. Work proposed in Aims 1-3 would provide indispensable fundamental information about the function of endogenous telomerase in adult cardiac progenitor cells. Conversely, work in Aim 4 would test potential therapeutic implications of telomerase and a telomere-capping protein with this auspicious population.
Max ERC Funding
2 497 576 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym COMBINE
Project From flies to humans combining whole genome screens and tissue specific gene targeting to identify novel pathways involved in cancer and metastases
Researcher (PI) Josef Martin Penninger
Host Institution (HI) INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Cancer care will be revolutionized over the next decade by the introduction of novel therapeutics that target the underlying molecular mechanisms of the disease. With the advent of human genetics, a plethora of genes have been correlated with human diseases such as cancer the SNP maps. Since the sequences are now available, the next big challenge is to determine the function of these genes in the context of the entire organism. Genetic animal models have proven to be extremely valuable to elucidate the essential functions of genes in normal physiology and the pathogenesis of disease. Using gene-targeted mice we have previously identified RANKL as a master gene of bone loss in arthritis, osteoporosis, and cancer cell migration and metastases and genes that control heart and kidney function; wound healing; diabetes; or lung injury Our primary goal is to use functional genomics in Drosophila and mice to understand cell transformation, invasion, and cancer metastases of epithelial tumors. The following projects are proposed: 1. Role of the key osteoclast differentiation factors RANKL-RANK and its downstream signalling cascade in the development of breast and prostate cancer. 2. Requirement of osteoclasts for bone metastases and stem cell niches using a new RANKfloxed allele; function of RANKL-RANK in local tumor cell invasion. 3. Role of RANKL-RANK in the central fever response to understand potential implications of future RANKL-RANK directed therapies. 4. Integration of gene targeting in mice with state-of-the art technologies in fly genetics; use of whole genome tissue-specific in vivo RNAi Drosophila libraries to identify essential and novel pathways for cancer pathogenesis using whole genome screens. 5. Role of TSPAN6, as a candidate lung metastasis gene. Identification of new cancer disease genes will allow us to design novel strategies for cancer treatment and will have ultimately impact on the basic understanding of cancer, metastases, and human health.
Summary
Cancer care will be revolutionized over the next decade by the introduction of novel therapeutics that target the underlying molecular mechanisms of the disease. With the advent of human genetics, a plethora of genes have been correlated with human diseases such as cancer the SNP maps. Since the sequences are now available, the next big challenge is to determine the function of these genes in the context of the entire organism. Genetic animal models have proven to be extremely valuable to elucidate the essential functions of genes in normal physiology and the pathogenesis of disease. Using gene-targeted mice we have previously identified RANKL as a master gene of bone loss in arthritis, osteoporosis, and cancer cell migration and metastases and genes that control heart and kidney function; wound healing; diabetes; or lung injury Our primary goal is to use functional genomics in Drosophila and mice to understand cell transformation, invasion, and cancer metastases of epithelial tumors. The following projects are proposed: 1. Role of the key osteoclast differentiation factors RANKL-RANK and its downstream signalling cascade in the development of breast and prostate cancer. 2. Requirement of osteoclasts for bone metastases and stem cell niches using a new RANKfloxed allele; function of RANKL-RANK in local tumor cell invasion. 3. Role of RANKL-RANK in the central fever response to understand potential implications of future RANKL-RANK directed therapies. 4. Integration of gene targeting in mice with state-of-the art technologies in fly genetics; use of whole genome tissue-specific in vivo RNAi Drosophila libraries to identify essential and novel pathways for cancer pathogenesis using whole genome screens. 5. Role of TSPAN6, as a candidate lung metastasis gene. Identification of new cancer disease genes will allow us to design novel strategies for cancer treatment and will have ultimately impact on the basic understanding of cancer, metastases, and human health.
Max ERC Funding
2 499 465 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym ICEBERG
Project Discovery of Type 2 Diabetes Targets
Researcher (PI) Juleen Rae Zierath
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary This proposal is focused on the identification and biological validation of the metabolic pathways and key regulatory genes that control insulin sensitivity in Type 2 diabetes mellitus (T2DM). We are focusing on skeletal muscle because it is quantitatively the most important tissue involved in maintaining glucose homeostasis under insulin-stimulated conditions and it is a major site of insulin resistance in T2DM. Our central hypothesis is that alterations in insulin signal transduction to glucose transport contribute to the profound impairment in whole body glucose homeostasis and T2DM pathogenesis. Identification of the defects in T2DM can lead to the development of new therapeutic strategies to prevent and cure this disease. The proposal is divided into two main objectives: We will apply: 1) target identification platforms including microarray, proteomics and bioinformatics to identify dysregulated genes in normal glucose tolerant versus T2DM subjects or genetically modified model systems and 2) functional genomics to assign a physiological role of the identified targets in Aim 1 using cellular and whole-body approaches. We will focus on the mitogen-activated protein kinase family, the energy-sensing enzyme AMP-activated protein kinase, and the lipid intermediate metabolizing enzyme diacylglycerol kinase delta. Our previous work indicates that these candidates play a role in the regulation of glucose metabolism, triglyceride storage, and energy homeostasis.
Summary
This proposal is focused on the identification and biological validation of the metabolic pathways and key regulatory genes that control insulin sensitivity in Type 2 diabetes mellitus (T2DM). We are focusing on skeletal muscle because it is quantitatively the most important tissue involved in maintaining glucose homeostasis under insulin-stimulated conditions and it is a major site of insulin resistance in T2DM. Our central hypothesis is that alterations in insulin signal transduction to glucose transport contribute to the profound impairment in whole body glucose homeostasis and T2DM pathogenesis. Identification of the defects in T2DM can lead to the development of new therapeutic strategies to prevent and cure this disease. The proposal is divided into two main objectives: We will apply: 1) target identification platforms including microarray, proteomics and bioinformatics to identify dysregulated genes in normal glucose tolerant versus T2DM subjects or genetically modified model systems and 2) functional genomics to assign a physiological role of the identified targets in Aim 1 using cellular and whole-body approaches. We will focus on the mitogen-activated protein kinase family, the energy-sensing enzyme AMP-activated protein kinase, and the lipid intermediate metabolizing enzyme diacylglycerol kinase delta. Our previous work indicates that these candidates play a role in the regulation of glucose metabolism, triglyceride storage, and energy homeostasis.
Max ERC Funding
2 500 000 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym MITO BY-PASS
Project Molecular by-pass therapy for mitochondrial dysfunction
Researcher (PI) Howard Trevor Jacobs
Host Institution (HI) TAMPEREEN YLIOPISTO
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Many eukaryotes, but not the higher metazoans such as vertebrates or arthropods, possess intrinsic by-pass systems that provide alternative routes for electron flow from NADH to oxygen. Whereas the standard mitochondrial OXPHOS system couples electron transport to proton pumping across the inner mitochondrial membrane, creating the proton gradient which is used to drive ATP synthesis and other energy-requiring processes, the by-pass enzymes are non-proton-pumping, and their activity is redox-regulated rather than subject to ATP requirements. My laboratory has engineered two of these by-pass enzymes, the single-subunit NADH dehydrogenase Ndi1p from yeast, and the alternative oxidase AOX from Ciona intestinalis, for expression in Drosophila and mammalian cells. Their expression is benign, and the enzymes appear to be almost inert, except under conditions of redox stress induced by OXPHOS toxins or mutations. The research set out in this proposal will explore the utility of these by-passes for alleviating metabolic stress in the whole organism and in specific tissues, arising from mitochondrial OXPHOS dysfunction. Specifically, I will test the ability of Ndi1p and AOX in Drosophila and in mammalian models to compensate for the toxicity of OXPHOS poisons, to complement disease-equivalent mutations impairing the assembly or function of the OXPHOS system, and to diminish the pathological excess production of reactive oxygen species seen in many neurodegenerative disorders associated with OXPHOS impairment, and under conditions of ischemia-reperfusion. The attenuation of endogenous mitochondrial ROS production by deployment of these by-pass enzymes also offers a novel route to testing the mitochondrial (oxyradical) theory of ageing.
Summary
Many eukaryotes, but not the higher metazoans such as vertebrates or arthropods, possess intrinsic by-pass systems that provide alternative routes for electron flow from NADH to oxygen. Whereas the standard mitochondrial OXPHOS system couples electron transport to proton pumping across the inner mitochondrial membrane, creating the proton gradient which is used to drive ATP synthesis and other energy-requiring processes, the by-pass enzymes are non-proton-pumping, and their activity is redox-regulated rather than subject to ATP requirements. My laboratory has engineered two of these by-pass enzymes, the single-subunit NADH dehydrogenase Ndi1p from yeast, and the alternative oxidase AOX from Ciona intestinalis, for expression in Drosophila and mammalian cells. Their expression is benign, and the enzymes appear to be almost inert, except under conditions of redox stress induced by OXPHOS toxins or mutations. The research set out in this proposal will explore the utility of these by-passes for alleviating metabolic stress in the whole organism and in specific tissues, arising from mitochondrial OXPHOS dysfunction. Specifically, I will test the ability of Ndi1p and AOX in Drosophila and in mammalian models to compensate for the toxicity of OXPHOS poisons, to complement disease-equivalent mutations impairing the assembly or function of the OXPHOS system, and to diminish the pathological excess production of reactive oxygen species seen in many neurodegenerative disorders associated with OXPHOS impairment, and under conditions of ischemia-reperfusion. The attenuation of endogenous mitochondrial ROS production by deployment of these by-pass enzymes also offers a novel route to testing the mitochondrial (oxyradical) theory of ageing.
Max ERC Funding
2 436 000 €
Duration
Start date: 2009-04-01, End date: 2015-03-31
Project acronym MORIAE
Project HUMAN AND MOUSE MODELS OF RHINOVIRUS INDUCED ACUTE ASTHMA EXACERBATIONS
Researcher (PI) Sebastian Lennox Johnston
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Asthma is the most common chronic respiratory disease and in many countries prevalence continues to rise. The major cause of asthma morbidity, mortality and health care costs are acute exacerbations, with rhinovirus infection the major cause. The aim of this application is to identify novel targets for the development of new more effective therapies for treatment and prevention of virus-induced asthma exacerbations, a disease area where there is a major unmet current clinical need. This proposal combines two unique state of the art novel models of acute exacerbations of asthma. First, a human model will be used to identify dysregulated genes/proteins and determine relationships with disease outcomes in vivo. This study will compare lower airway responses between asthmatic and control subjects undergoing rhinovirus experimental infection. This will have the dual advantage of investigating mechanisms in the most natural model possible, as well as developing a better model for testing novel therapeutic approaches. The second utilizes a unique new mouse model of rhinovirus infection in which causal relationships with disease outcomes can be investigated in vivo. This will be performed using gene-knockout mice, blocking antibodies, siRNA, pharmacologic inhibition and/or over-expression in genes in a novel mouse model of rhinovirus exacerbation. Any genes/proteins shown to be dysregulated and related to disease outcomes in the human model, AND causally related to disease outcomes in the mouse in vivo model will be very strong candidates for immediate translation of approaches to correct the dysregulation in proof of concept pivotal human intervention studies. The development of a new low dose challenge human model proposed will also provide a new and optimal model of naturally occurring exacerbations, in which such proof of concept pivotal human intervention studies can be carried out.
Summary
Asthma is the most common chronic respiratory disease and in many countries prevalence continues to rise. The major cause of asthma morbidity, mortality and health care costs are acute exacerbations, with rhinovirus infection the major cause. The aim of this application is to identify novel targets for the development of new more effective therapies for treatment and prevention of virus-induced asthma exacerbations, a disease area where there is a major unmet current clinical need. This proposal combines two unique state of the art novel models of acute exacerbations of asthma. First, a human model will be used to identify dysregulated genes/proteins and determine relationships with disease outcomes in vivo. This study will compare lower airway responses between asthmatic and control subjects undergoing rhinovirus experimental infection. This will have the dual advantage of investigating mechanisms in the most natural model possible, as well as developing a better model for testing novel therapeutic approaches. The second utilizes a unique new mouse model of rhinovirus infection in which causal relationships with disease outcomes can be investigated in vivo. This will be performed using gene-knockout mice, blocking antibodies, siRNA, pharmacologic inhibition and/or over-expression in genes in a novel mouse model of rhinovirus exacerbation. Any genes/proteins shown to be dysregulated and related to disease outcomes in the human model, AND causally related to disease outcomes in the mouse in vivo model will be very strong candidates for immediate translation of approaches to correct the dysregulation in proof of concept pivotal human intervention studies. The development of a new low dose challenge human model proposed will also provide a new and optimal model of naturally occurring exacerbations, in which such proof of concept pivotal human intervention studies can be carried out.
Max ERC Funding
2 497 761 €
Duration
Start date: 2009-04-01, End date: 2014-03-31
Project acronym NEURONAGE
Project Molecular Basis of Neuronal Ageing
Researcher (PI) Nektarios Tavernarakis
Host Institution (HI) IDRYMA TECHNOLOGIAS KAI EREVNAS
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Ageing is associated with marked decrease of neuronal function and increased susceptibility to neurodegeneration, in organisms as diverse as the lowly worm Caenorhabditis elegans and humans. Although, age-related deterioration of the nervous system is a universal phenomenon, its cellular and molecular underpinnings remain obscure. What mechanisms are responsible for the detrimental effects of ageing on neuronal function? The aim of the proposed research programme is to address this fundamental problem. We will implement an interdisciplinary approach, combining the power of C. elegans, a highly malleable genetic model which offers a precisely defined nervous system, with state-of-the-art microfluidics and optical imaging technologies, to manipulate and monitor neuronal activity during ageing, in vivo. Our objectives are four-fold. First, develop a microfluidics platform for high-throughput manipulation and imaging of specific neurons in individual animals, in vivo. Second, use the platform to monitor neuronal function during ageing in isogenic populations of wild type animals, long-lived mutants and animals under caloric restriction, a condition known to extend lifespan from yeast to primates. Third, examine how ageing modulates susceptibility to neuronal damage in nematode models of human neurodegenerative disorders. Fourth, conduct both forward and reverse genetic screens for modifiers of resistance to ageing-inflicted neuronal function decline. We will seek to identify and thoroughly characterize genes and molecular pathways involved in neuron deterioration during ageing. Ultimately, we will investigate the functional conservation of key isolated factors in more complex ageing models such as Drosophila and the mouse. Together, these studies will lead to an unprecedented understanding of age-related breakdown of neuronal function and will provide critical insights with broad relevance to human health and quality of life.
Summary
Ageing is associated with marked decrease of neuronal function and increased susceptibility to neurodegeneration, in organisms as diverse as the lowly worm Caenorhabditis elegans and humans. Although, age-related deterioration of the nervous system is a universal phenomenon, its cellular and molecular underpinnings remain obscure. What mechanisms are responsible for the detrimental effects of ageing on neuronal function? The aim of the proposed research programme is to address this fundamental problem. We will implement an interdisciplinary approach, combining the power of C. elegans, a highly malleable genetic model which offers a precisely defined nervous system, with state-of-the-art microfluidics and optical imaging technologies, to manipulate and monitor neuronal activity during ageing, in vivo. Our objectives are four-fold. First, develop a microfluidics platform for high-throughput manipulation and imaging of specific neurons in individual animals, in vivo. Second, use the platform to monitor neuronal function during ageing in isogenic populations of wild type animals, long-lived mutants and animals under caloric restriction, a condition known to extend lifespan from yeast to primates. Third, examine how ageing modulates susceptibility to neuronal damage in nematode models of human neurodegenerative disorders. Fourth, conduct both forward and reverse genetic screens for modifiers of resistance to ageing-inflicted neuronal function decline. We will seek to identify and thoroughly characterize genes and molecular pathways involved in neuron deterioration during ageing. Ultimately, we will investigate the functional conservation of key isolated factors in more complex ageing models such as Drosophila and the mouse. Together, these studies will lead to an unprecedented understanding of age-related breakdown of neuronal function and will provide critical insights with broad relevance to human health and quality of life.
Max ERC Funding
2 376 000 €
Duration
Start date: 2009-05-01, End date: 2015-04-30
Project acronym SIRTUINS
Project Phenogenomics of sirtuin corepressor family
Researcher (PI) Johan Auwerx
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary By modulating the activity of transcription factors, cofactors influence cellular and organismal metabolic pathways. Recently the role of the sirtuin cofactor gene family received a lot of attention in this context, as their beneficial impact on longevity was linked to effects on metabolic control. Most sirtuins catalyze deacetylation reactions that are tightly linked to cellular energy (NAD+) levels. To ascertain the tissue-specific contributions of sirtuins in metabolism, we propose here to: 1) identify novel deacetylation targets for the sirtuins; 2) generate and characterize genetically engineered mouse models (GEMMs) with somatic mutations in the 7 sirtuin genes in liver, muscle and adipose tissue, key metabolic tissues; 3) study mouse models with natural genetic variation in sirtuin expression, such as found in genetic reference populations (GRPs), like the BxD recombinant inbred mouse lines; and 4) validate the relevance of sirtuin signaling for human metabolism through clinical genetic studies. As the goal is to progress towards the treatment and prevention of metabolic diseases in humans, GEMMs are optimized to study the actions of isolated genetic loci and are thus insufficient to characterize polygenic networks and genetic interactions. Moreover environmental factors can impact on the manifestations of the genotype or phenocopy the genetically produced phenotype. Thus, to dissect complex genetic traits, experimental models, like GRPs, that imitate the genetic structure of human populations provide complimentary information to that obtained from GEMMs. As we will combine data generated using directional genetic strategies in GEMMs with a high-throughput phenogenomic analysis of GRPs, our approach merges the benefits of clear-cut results of single gene perturbations in a given tissue with subtle alterations that result from natural innumerable allelic variants. This will ultimately favor the definition of the role of the sirtuins in metabolic homeostasis.
Summary
By modulating the activity of transcription factors, cofactors influence cellular and organismal metabolic pathways. Recently the role of the sirtuin cofactor gene family received a lot of attention in this context, as their beneficial impact on longevity was linked to effects on metabolic control. Most sirtuins catalyze deacetylation reactions that are tightly linked to cellular energy (NAD+) levels. To ascertain the tissue-specific contributions of sirtuins in metabolism, we propose here to: 1) identify novel deacetylation targets for the sirtuins; 2) generate and characterize genetically engineered mouse models (GEMMs) with somatic mutations in the 7 sirtuin genes in liver, muscle and adipose tissue, key metabolic tissues; 3) study mouse models with natural genetic variation in sirtuin expression, such as found in genetic reference populations (GRPs), like the BxD recombinant inbred mouse lines; and 4) validate the relevance of sirtuin signaling for human metabolism through clinical genetic studies. As the goal is to progress towards the treatment and prevention of metabolic diseases in humans, GEMMs are optimized to study the actions of isolated genetic loci and are thus insufficient to characterize polygenic networks and genetic interactions. Moreover environmental factors can impact on the manifestations of the genotype or phenocopy the genetically produced phenotype. Thus, to dissect complex genetic traits, experimental models, like GRPs, that imitate the genetic structure of human populations provide complimentary information to that obtained from GEMMs. As we will combine data generated using directional genetic strategies in GEMMs with a high-throughput phenogenomic analysis of GRPs, our approach merges the benefits of clear-cut results of single gene perturbations in a given tissue with subtle alterations that result from natural innumerable allelic variants. This will ultimately favor the definition of the role of the sirtuins in metabolic homeostasis.
Max ERC Funding
2 485 000 €
Duration
Start date: 2009-02-01, End date: 2014-01-31
