Project acronym ADIPODIF
Project Adipocyte Differentiation and Metabolic Functions in Obesity and Type 2 Diabetes
Researcher (PI) Christian Wolfrum
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Starting Grant (StG), LS6, ERC-2007-StG
Summary Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.
Summary
Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.
Max ERC Funding
1 607 105 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym AGALT
Project Asymptotic Geometric Analysis and Learning Theory
Researcher (PI) Shahar Mendelson
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Country Israel
Call Details Starting Grant (StG), PE1, ERC-2007-StG
Summary In a typical learning problem one tries to approximate an unknown function by a function from a given class using random data, sampled according to an unknown measure. In this project we will be interested in parameters that govern the complexity of a learning problem. It turns out that this complexity is determined by the geometry of certain sets in high dimension that are connected to the given class (random coordinate projections of the class). Thus, one has to understand the structure of these sets as a function of the dimension - which is given by the cardinality of the random sample. The resulting analysis leads to many theoretical questions in Asymptotic Geometric Analysis, Probability (most notably, Empirical Processes Theory) and Combinatorics, which are of independent interest beyond the application to Learning Theory. Our main goal is to describe the role of various complexity parameters involved in a learning problem, to analyze the connections between them and to investigate the way they determine the geometry of the relevant high dimensional sets. Some of the questions we intend to tackle are well known open problems and making progress towards their solution will have a significant theoretical impact. Moreover, this project should lead to a more complete theory of learning and is likely to have some practical impact, for example, in the design of more efficient learning algorithms.
Summary
In a typical learning problem one tries to approximate an unknown function by a function from a given class using random data, sampled according to an unknown measure. In this project we will be interested in parameters that govern the complexity of a learning problem. It turns out that this complexity is determined by the geometry of certain sets in high dimension that are connected to the given class (random coordinate projections of the class). Thus, one has to understand the structure of these sets as a function of the dimension - which is given by the cardinality of the random sample. The resulting analysis leads to many theoretical questions in Asymptotic Geometric Analysis, Probability (most notably, Empirical Processes Theory) and Combinatorics, which are of independent interest beyond the application to Learning Theory. Our main goal is to describe the role of various complexity parameters involved in a learning problem, to analyze the connections between them and to investigate the way they determine the geometry of the relevant high dimensional sets. Some of the questions we intend to tackle are well known open problems and making progress towards their solution will have a significant theoretical impact. Moreover, this project should lead to a more complete theory of learning and is likely to have some practical impact, for example, in the design of more efficient learning algorithms.
Max ERC Funding
750 000 €
Duration
Start date: 2009-03-01, End date: 2014-02-28
Project acronym BACTERIAL SPORES
Project Investigating the Nature of Bacterial Spores
Researcher (PI) Sigal Ben-Yehuda
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.
Summary
When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.
Max ERC Funding
1 630 000 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym ERNBPTC
Project Expression regulatory networks: beyond promoters and transcription control
Researcher (PI) Yitzhak Pilpel
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary "Gene expression in living cells is a most intricate molecular process, occurring in stages, each of which is regulated by a diversity of mechanisms. Among the various stages leading to gene expression, only transcription is relatively well understood, thanks to Genomics and bioinformatics. In contrast to the vast amounts of genome-wide data and a growing understanding of the structure of networks controlling transcription, we still lack quantitative, genome-wide knowledge of the mechanisms underlying regulation of mRNA degradation and translation. Among the unknowns are the identity of the regulators, their kinetic modes of action, and their means of interaction with the sequence features that make-up their targets; how these target combine to produce a higher level ""grammar"" is also unknown. An important part of the project is dedicated to generating genome-wide experimental data that will form the basis for quantitative and more comprehensive analysis of gene expression. Specifically, the primary objectives of our proposed research plan are: 1) to advance our understanding of the transcriptome, by deciphering the code regulating mRNA decay 2) to break the code which controls protein translation efficiency 3) to understand how mRNA degradation and translation efficiency determine noise in protein expression levels. The proposed strategy is based on an innovative combination of computational prediction, synthetic gene design, and genome-wide data acquisition, all culminating in extensive data analysis, mathematical modeling and focused experiments. This highly challenging, multidisciplinary project is likely to greatly enhance our knowledge of the various modes by which organisms regulate expression of their genomes, how these regulatory mechanisms are interrelated, how they generate precise response to environmental challenges and how they have evolved over time."
Summary
"Gene expression in living cells is a most intricate molecular process, occurring in stages, each of which is regulated by a diversity of mechanisms. Among the various stages leading to gene expression, only transcription is relatively well understood, thanks to Genomics and bioinformatics. In contrast to the vast amounts of genome-wide data and a growing understanding of the structure of networks controlling transcription, we still lack quantitative, genome-wide knowledge of the mechanisms underlying regulation of mRNA degradation and translation. Among the unknowns are the identity of the regulators, their kinetic modes of action, and their means of interaction with the sequence features that make-up their targets; how these target combine to produce a higher level ""grammar"" is also unknown. An important part of the project is dedicated to generating genome-wide experimental data that will form the basis for quantitative and more comprehensive analysis of gene expression. Specifically, the primary objectives of our proposed research plan are: 1) to advance our understanding of the transcriptome, by deciphering the code regulating mRNA decay 2) to break the code which controls protein translation efficiency 3) to understand how mRNA degradation and translation efficiency determine noise in protein expression levels. The proposed strategy is based on an innovative combination of computational prediction, synthetic gene design, and genome-wide data acquisition, all culminating in extensive data analysis, mathematical modeling and focused experiments. This highly challenging, multidisciplinary project is likely to greatly enhance our knowledge of the various modes by which organisms regulate expression of their genomes, how these regulatory mechanisms are interrelated, how they generate precise response to environmental challenges and how they have evolved over time."
Max ERC Funding
1 320 000 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym PIMCYV
Project Physiological Interactions between Marine Cyanobacteria and their Viruses
Researcher (PI) Debbie Lindell
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Country Israel
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary Viruses (phages) influence many aspects of microbial processes including the population dynamics, diversity and evolution of their hosts. Yet we know practically nothing about the physiological interactions between hosts and phages during infection even though it is the outcome of these very interactions that affects the above-mentioned processes. Using marine cyanobacteria as a model system I propose to study the physiological interactions between ecologically important microbes and the phages that infect them to gain an understanding of the mechanisms through which they impact microbial ecology processes. Cyanobacteria are an important component of marine phytoplankton and contribute significantly to primary production in vast regions of the world’s oceans. The specific objectives of this proposed study are to: (1) Identify phage genes involved in taking over host metabolic processes; (2) Assess the fitness advantage to the phage provided by bacterial-like genes in phage genomes; (3) Develop a genetic manipulation system for cyanobacterial phages to determine the function of genes in (1) and (2); (4) Discover genes functioning in host defense mechanisms in diverse cyanobacterial-phage systems using whole-genome expression analysis and the generation of phage resistant strains; (5) Determine the impact of genes identified in (4) above on host fitness and phage development during infection. Discovery of the mechanisms employed by phage for taking over host metabolic processes and the defense mechanisms set into motion by the host to overcome phage infection will provide insight into how such interactions influence the diversity and evolution of both cyanobacteria and their phages. Furthermore, this study has high potential for uncovering new bacterial defense mechanisms as well as the discovery of novel viral mechanisms for shutting down bacterial metabolic processes, both of which may also have future practical applications.
Summary
Viruses (phages) influence many aspects of microbial processes including the population dynamics, diversity and evolution of their hosts. Yet we know practically nothing about the physiological interactions between hosts and phages during infection even though it is the outcome of these very interactions that affects the above-mentioned processes. Using marine cyanobacteria as a model system I propose to study the physiological interactions between ecologically important microbes and the phages that infect them to gain an understanding of the mechanisms through which they impact microbial ecology processes. Cyanobacteria are an important component of marine phytoplankton and contribute significantly to primary production in vast regions of the world’s oceans. The specific objectives of this proposed study are to: (1) Identify phage genes involved in taking over host metabolic processes; (2) Assess the fitness advantage to the phage provided by bacterial-like genes in phage genomes; (3) Develop a genetic manipulation system for cyanobacterial phages to determine the function of genes in (1) and (2); (4) Discover genes functioning in host defense mechanisms in diverse cyanobacterial-phage systems using whole-genome expression analysis and the generation of phage resistant strains; (5) Determine the impact of genes identified in (4) above on host fitness and phage development during infection. Discovery of the mechanisms employed by phage for taking over host metabolic processes and the defense mechanisms set into motion by the host to overcome phage infection will provide insight into how such interactions influence the diversity and evolution of both cyanobacteria and their phages. Furthermore, this study has high potential for uncovering new bacterial defense mechanisms as well as the discovery of novel viral mechanisms for shutting down bacterial metabolic processes, both of which may also have future practical applications.
Max ERC Funding
1 582 200 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym TRANSCRIPTION_REG
Project A combined experimental and computational approach for quantitative and mechanistic understanding of transcriptional regulation
Researcher (PI) Eran Segal
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary The complex functions of a living cell are carried out through the coordinated activity of many genes. Since transcription is a key step in establishing such coordinated activity, much effort was devoted to its study, and tremendous progress was made in identifying many of the transcription factors and regulatory DNA elements involved in the regulation of specific systems. However, very few attempts were made at going beyond these phenomenological and qualitative descriptions. Consequently, we are far from a quantitative and predictive understanding of transcriptional regulation. Through this program, I aim to develop a mechanistic understanding of transcriptional regulation, and for the first time model the entire process. We wish to go much beyond identifying and qualitatively describing the involved components, and arrive at a quantitative understanding of how transcriptional programs are encoded in the DNA sequences. To this end, my team and I will first work to mechanistically understand various building blocks of the transcriptional system, including: mechanisms of activation and repression; binding cooperativity; binding competition; transcription factors and chromatin interplay; architectural features of promoters that are important for its function; and the transcription functions “computed” by promoters. Since existing data are clearly insufficient for addressing such questions, I have opened an experimental lab and began to assemble a multidisciplinary team of scientists whose expertise span the experimental biology, computer science, physics, statistics, and mathematics disciplines, that will work synergistically to generate the appropriate data, analyze it, and use it to construct and experimentally validate models for the above transcriptional building blocks. We will then integrate all the insights gained into unified and quantitative models that should significantly enhance our understanding of the mechanistic workings of transcriptional regulation.
Summary
The complex functions of a living cell are carried out through the coordinated activity of many genes. Since transcription is a key step in establishing such coordinated activity, much effort was devoted to its study, and tremendous progress was made in identifying many of the transcription factors and regulatory DNA elements involved in the regulation of specific systems. However, very few attempts were made at going beyond these phenomenological and qualitative descriptions. Consequently, we are far from a quantitative and predictive understanding of transcriptional regulation. Through this program, I aim to develop a mechanistic understanding of transcriptional regulation, and for the first time model the entire process. We wish to go much beyond identifying and qualitatively describing the involved components, and arrive at a quantitative understanding of how transcriptional programs are encoded in the DNA sequences. To this end, my team and I will first work to mechanistically understand various building blocks of the transcriptional system, including: mechanisms of activation and repression; binding cooperativity; binding competition; transcription factors and chromatin interplay; architectural features of promoters that are important for its function; and the transcription functions “computed” by promoters. Since existing data are clearly insufficient for addressing such questions, I have opened an experimental lab and began to assemble a multidisciplinary team of scientists whose expertise span the experimental biology, computer science, physics, statistics, and mathematics disciplines, that will work synergistically to generate the appropriate data, analyze it, and use it to construct and experimentally validate models for the above transcriptional building blocks. We will then integrate all the insights gained into unified and quantitative models that should significantly enhance our understanding of the mechanistic workings of transcriptional regulation.
Max ERC Funding
1 005 600 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
