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 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 FRONTIERS OF RNAI
Project The role of RNA silencing in immunity and development in eukaryotes
Researcher (PI) Olivier Voinnet
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary RNA silencing is a pan-eukaryotic gene regulation process that involves RNA molecules 19-30nt in length. These molecules are produced by RNAse-III proteins in the Dicer family and engage into sequence-specific regulation of complementary DNA or RNA upon their incorporation into effector complexes. RNA silencing serves essential roles in biology but the molecular bases of its mechanisms are still poorly understood. One major aspect of the proposed project is to decipher genetically the composition of RNA silencing effector complexes and to understand how those complexes orchestrate the regulation of fundamental processes involved in cell differentiation, notably the process of dosage compensation during chromosome X inactivation in mammals. The second aspect is part of our ongoing efforts to understand the implication of small RNAs in plant and animal innate immunity, their impact on pathogen’s fitness and evolution, and how pathogens counteract small RNA-directed immune pathways.
Summary
RNA silencing is a pan-eukaryotic gene regulation process that involves RNA molecules 19-30nt in length. These molecules are produced by RNAse-III proteins in the Dicer family and engage into sequence-specific regulation of complementary DNA or RNA upon their incorporation into effector complexes. RNA silencing serves essential roles in biology but the molecular bases of its mechanisms are still poorly understood. One major aspect of the proposed project is to decipher genetically the composition of RNA silencing effector complexes and to understand how those complexes orchestrate the regulation of fundamental processes involved in cell differentiation, notably the process of dosage compensation during chromosome X inactivation in mammals. The second aspect is part of our ongoing efforts to understand the implication of small RNAs in plant and animal innate immunity, their impact on pathogen’s fitness and evolution, and how pathogens counteract small RNA-directed immune pathways.
Max ERC Funding
900 000 €
Duration
Start date: 2008-08-01, End date: 2012-07-31
Project acronym INSPIRE
Project Interhemispheric stimulation promotes reading: two brains are better then one
Researcher (PI) Michal Lavidor
Host Institution (HI) BAR ILAN UNIVERSITY
Country Israel
Call Details Starting Grant (StG), SH3, ERC-2007-StG
Summary The ultimate goal of INSPIRE is to develop Transcranial Magnetic Stimulation (TMS)-based and training protocols that will improve semantic skills and creative thinking of healthy and impaired individuals by manipulating the balance between the hemispheres while they process language. Although ambitious and revolutionary, this goal is fundamental to conceptions of language processing and functional lateralization in the human brain. Specific objectives are: (1) To investigate how do semantic processes interact with creative thinking, particularly in the right hemisphere (RH). (2) To generate (reversible and temporary) localized functional impairment in healthy participants in order to specify the cortical areas involved in normal semantic processing. In particular, inhibitory TMS protocols will be used to investigate the role of the RH in processing remote associations, metaphors, sarcasm and subordinate meanings of ambiguous words. Complementary TMS-induced impairments are predicted for left hemisphere (LH) stimulation in language areas. (3) To improve RH semantic abilities and creative thinking by targeting excitatory TMS protocols at the regions of interest, and by enhancing the functioning of the homologue un-stimulated cortex with inhibitory protocols via disinhibition. (4) To improve RH semantic abilities and creative thinking by 'left' and 'right' hemisphere training. (5) To apply the research findings of objectives 1-4 above to aphasia, schizophrenia and RH brain damaged patients in order to improve their semantic skills. Prof. Lavidor is now moving back to Israel with her family after a long stay in the UK. The ERC support is requested for the re-establishment of an active and successful TMS lab in Israel, similar to the one Lavidor set up in the UK. The INSPIRE project, if funded, will allow her to build a new generation of inspired research students in her new lab, trained for excellence by Lavidor, who won the 2006 Marie Curie Excellence Award
Summary
The ultimate goal of INSPIRE is to develop Transcranial Magnetic Stimulation (TMS)-based and training protocols that will improve semantic skills and creative thinking of healthy and impaired individuals by manipulating the balance between the hemispheres while they process language. Although ambitious and revolutionary, this goal is fundamental to conceptions of language processing and functional lateralization in the human brain. Specific objectives are: (1) To investigate how do semantic processes interact with creative thinking, particularly in the right hemisphere (RH). (2) To generate (reversible and temporary) localized functional impairment in healthy participants in order to specify the cortical areas involved in normal semantic processing. In particular, inhibitory TMS protocols will be used to investigate the role of the RH in processing remote associations, metaphors, sarcasm and subordinate meanings of ambiguous words. Complementary TMS-induced impairments are predicted for left hemisphere (LH) stimulation in language areas. (3) To improve RH semantic abilities and creative thinking by targeting excitatory TMS protocols at the regions of interest, and by enhancing the functioning of the homologue un-stimulated cortex with inhibitory protocols via disinhibition. (4) To improve RH semantic abilities and creative thinking by 'left' and 'right' hemisphere training. (5) To apply the research findings of objectives 1-4 above to aphasia, schizophrenia and RH brain damaged patients in order to improve their semantic skills. Prof. Lavidor is now moving back to Israel with her family after a long stay in the UK. The ERC support is requested for the re-establishment of an active and successful TMS lab in Israel, similar to the one Lavidor set up in the UK. The INSPIRE project, if funded, will allow her to build a new generation of inspired research students in her new lab, trained for excellence by Lavidor, who won the 2006 Marie Curie Excellence Award
Max ERC Funding
638 400 €
Duration
Start date: 2008-10-01, End date: 2012-09-30
Project acronym MRNA QUALITY
Project Quality control of gene expression: mechanisms for recognition and elimination of nonsense mRNA
Researcher (PI) Oliver Muehlemann
Host Institution (HI) UNIVERSITAET BERN
Country Switzerland
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Analogous to quality control checks along the assembly line in industrial manufacturing processes, cells possess multiple quality control systems that ensure accurate expression of the genetic information throughout the intricate chain of biochemical reactions. “Nonsense-mediated mRNA decay” (NMD) represents a quality control mechanism that recognizes and degrades mRNAs of which the protein coding sequence is truncated by the presence of a premature termination codon (PTC). By eliminating these defective mRNAs with crippled protein-coding capacity, NMD substantially reduces the synthesis of potentially deleterious truncated proteins. Given that 30 % of all known disease-causing mutations in humans lead to the production of a nonsense mRNA, NMD serves as an important modulator of the clinical manifestations of genetic diseases, and manipulating NMD therefore represents a promising strategy for future therapies of many genetic disorders. However, the underlying molecular mechanisms of NMD are currently not well understood. One goal of our research is to understand at the molecular level how PTCs are recognized and distinguished from correct termination codons and how this recognition of nonsense mRNAs subsequently triggers their rapid degradation. In addition to triggering NMD, we have recently discovered that PTCs in certain immunoglobulin genes can also lead to the transcriptional silencing of the corresponding gene. We now search for the biological relevance of this novel quality control mechanism termed “nonsense-mediated transcriptional gene silencing” (NMTGS) and want to identify the involved molecules and their interactions. Using mainly mammalian cell cultures, we study the effect on the expression of engineered NMD and NMTGS reporter genes upon various treatments of the cells. State-of-the-art biochemical and molecular biology techniques are employed with the goal to further our understanding of these processes and their regulation at the molecular level.
Summary
Analogous to quality control checks along the assembly line in industrial manufacturing processes, cells possess multiple quality control systems that ensure accurate expression of the genetic information throughout the intricate chain of biochemical reactions. “Nonsense-mediated mRNA decay” (NMD) represents a quality control mechanism that recognizes and degrades mRNAs of which the protein coding sequence is truncated by the presence of a premature termination codon (PTC). By eliminating these defective mRNAs with crippled protein-coding capacity, NMD substantially reduces the synthesis of potentially deleterious truncated proteins. Given that 30 % of all known disease-causing mutations in humans lead to the production of a nonsense mRNA, NMD serves as an important modulator of the clinical manifestations of genetic diseases, and manipulating NMD therefore represents a promising strategy for future therapies of many genetic disorders. However, the underlying molecular mechanisms of NMD are currently not well understood. One goal of our research is to understand at the molecular level how PTCs are recognized and distinguished from correct termination codons and how this recognition of nonsense mRNAs subsequently triggers their rapid degradation. In addition to triggering NMD, we have recently discovered that PTCs in certain immunoglobulin genes can also lead to the transcriptional silencing of the corresponding gene. We now search for the biological relevance of this novel quality control mechanism termed “nonsense-mediated transcriptional gene silencing” (NMTGS) and want to identify the involved molecules and their interactions. Using mainly mammalian cell cultures, we study the effect on the expression of engineered NMD and NMTGS reporter genes upon various treatments of the cells. State-of-the-art biochemical and molecular biology techniques are employed with the goal to further our understanding of these processes and their regulation at the molecular level.
Max ERC Funding
1 300 000 €
Duration
Start date: 2008-06-01, End date: 2013-05-31
Project acronym NMU-LIPIDS
Project Biomimetic Lipid Structures on Nano- and Microfluidic Platforms
Researcher (PI) Petra Stephanie Dittrich
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Starting Grant (StG), PE6, ERC-2007-StG
Summary The projects aim at the formation, manipulation, and analysis of three-dimensional lipid membrane structures on micro- and nano-structured platforms. The goal is to develop a novel methodology to design and create simple artificial cells and cell organelles, bio-hybrid cells, and bio-mimicking membrane networks, which could be an entirely novel tool for cell analysis, and promises fascinating prospects for cell manipulation, biotechnology, pharmacy and material sciences. The basis of the projects is formed by an unconventional concept that involves two current cutting-edge fabrication technologies, i.e. the so-called top-down and bottom-up approaches. The combination of the two approaches, with respect to both engineering methods and biological applications, opens the door to overcome current limitations in the creation of complex soft matter objects in micro- and nanometre dimension. The key method is a recently developed micro-extrusion process. It relies, on the one hand, on the ability of the lipid molecules to self-assemble (“bottom-up”). On the other hand, photolithography processes (“top-down”) are utilized to fabricate microchips, in which shape transformation, handling and analysis of the lipid structures are performed. The proposed engineering process will enable, for the first time, to precisely design composition, size and morphology of complex membrane structures. It will provide the requirements to design an artificial cell of reasonable complexity (“bottom-up”). One main emphasis is the creation of unique bio-hybrid systems, in which artificial membrane structures are connected to living cells, or in which natural membranes of cells are integrated within artificial systems (“top-down”). This highly interdisciplinary study will further include fundamental studies on membrane properties, engineering aspects to generate novel soft-matter devices, and the development of analytical methods and lipid sensors based on micro- and nanostructured chips.
Summary
The projects aim at the formation, manipulation, and analysis of three-dimensional lipid membrane structures on micro- and nano-structured platforms. The goal is to develop a novel methodology to design and create simple artificial cells and cell organelles, bio-hybrid cells, and bio-mimicking membrane networks, which could be an entirely novel tool for cell analysis, and promises fascinating prospects for cell manipulation, biotechnology, pharmacy and material sciences. The basis of the projects is formed by an unconventional concept that involves two current cutting-edge fabrication technologies, i.e. the so-called top-down and bottom-up approaches. The combination of the two approaches, with respect to both engineering methods and biological applications, opens the door to overcome current limitations in the creation of complex soft matter objects in micro- and nanometre dimension. The key method is a recently developed micro-extrusion process. It relies, on the one hand, on the ability of the lipid molecules to self-assemble (“bottom-up”). On the other hand, photolithography processes (“top-down”) are utilized to fabricate microchips, in which shape transformation, handling and analysis of the lipid structures are performed. The proposed engineering process will enable, for the first time, to precisely design composition, size and morphology of complex membrane structures. It will provide the requirements to design an artificial cell of reasonable complexity (“bottom-up”). One main emphasis is the creation of unique bio-hybrid systems, in which artificial membrane structures are connected to living cells, or in which natural membranes of cells are integrated within artificial systems (“top-down”). This highly interdisciplinary study will further include fundamental studies on membrane properties, engineering aspects to generate novel soft-matter devices, and the development of analytical methods and lipid sensors based on micro- and nanostructured chips.
Max ERC Funding
1 941 000 €
Duration
Start date: 2008-07-01, End date: 2014-06-30
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 PLANT-MEMB-TRAFF
Project Plant endomembrane trafficking in physiology and development
Researcher (PI) Niko Geldner
Host Institution (HI) UNIVERSITE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Understanding the structure and function of endomembrane compartments is central to a mechanistic understanding of eukaryotic cell behavior. Multi-cellular organisms show an increased complexity and specialization in their endomembrane trafficking pathways. Higher plants have independently developed multi-cellularity and show a differently structured, but highly complex endomembrane system that regulates numerous, fundamental processes, such as cell wall composition, plant nutrition or immune responses. However, the specificities of plant endomembrane trafficking are only insufficiently addressed by homology-based approaches, which are inherently biased and limited to modules and pathways that are conserved between animals/yeast and plants. I propose to address this by undertaking forward genetic approaches for regulators of endocytic trafficking in Arabidopis with newly developed tools. In addition, I will establish the root endodermis as a model to address the mechanism of epithelial polarity establishment in plants. Epithelia are a fundamental feature of multi-cellular organisms and have independently evolved in plants and animals. The root endodermis is a tissue of central importance for plant nutrition. It is accessible to analysis and displays all the defining features of an epithelium. Studying the endodermis will allow me to investigate how independent or conserved the mechanisms of epithelial polarity are. Apart from the immediate interest for a number of plant developmental and adaptive responses, I contend that both parts of my proposal are also of general, fundamental interest. Current comparisons between yeast and animals do not give us any reliable and coherent idea about what is truly fundamental or derived in eukaryotic membrane organization. Unbiased research on plant membrane trafficking will provide insight into an additional, divergent type of eukaryotic cell and allow a better appreciation of the evolution of eukaryotic membrane organization.
Summary
Understanding the structure and function of endomembrane compartments is central to a mechanistic understanding of eukaryotic cell behavior. Multi-cellular organisms show an increased complexity and specialization in their endomembrane trafficking pathways. Higher plants have independently developed multi-cellularity and show a differently structured, but highly complex endomembrane system that regulates numerous, fundamental processes, such as cell wall composition, plant nutrition or immune responses. However, the specificities of plant endomembrane trafficking are only insufficiently addressed by homology-based approaches, which are inherently biased and limited to modules and pathways that are conserved between animals/yeast and plants. I propose to address this by undertaking forward genetic approaches for regulators of endocytic trafficking in Arabidopis with newly developed tools. In addition, I will establish the root endodermis as a model to address the mechanism of epithelial polarity establishment in plants. Epithelia are a fundamental feature of multi-cellular organisms and have independently evolved in plants and animals. The root endodermis is a tissue of central importance for plant nutrition. It is accessible to analysis and displays all the defining features of an epithelium. Studying the endodermis will allow me to investigate how independent or conserved the mechanisms of epithelial polarity are. Apart from the immediate interest for a number of plant developmental and adaptive responses, I contend that both parts of my proposal are also of general, fundamental interest. Current comparisons between yeast and animals do not give us any reliable and coherent idea about what is truly fundamental or derived in eukaryotic membrane organization. Unbiased research on plant membrane trafficking will provide insight into an additional, divergent type of eukaryotic cell and allow a better appreciation of the evolution of eukaryotic membrane organization.
Max ERC Funding
1 199 889 €
Duration
Start date: 2008-04-01, End date: 2013-03-31
Project acronym SINGLEMOLFOLDING
Project Towards Protein Folding in the Cell with Single Molecule Spectroscopy
Researcher (PI) Benjamin Schuler
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Many aspects of the physical principles governing protein folding in vitro have been elucidated in the past decades. At the same time, a large number of cellular components involved in protein folding in vivo have been identified. But our mechanistic understanding of how these cellular components affect the energy landscape of the folding process has remained very limited, largely due to a lack of suitable methods. An opportunity to bridge this gap is single molecule fluorescence spectroscopy in combination with Förster resonance energy transfer (FRET), a new technique that allows the investigation of distance distributions and dynamics of individual protein molecules even in complex and heterogeneous environments. In a multi-disciplinary project employing methods ranging from molecular biology and protein biochemistry to optics, microfluidic mixing, and development of instrumentation and software, we plan to use single molecule spectroscopy for investigating the question how proteins find their native three-dimensional structure in a cell. Our initial focus will be on molecular chaperones, which assist protein folding in vivo, but the approach is applicable to a wide range of related phenomena and will be extended to other cellular components. This project is thus expected to nucleate a comprehensive biophysical analysis of intracellular protein folding and dynamics, eventually within live cells. A detailed investigation of these processes will be crucial for understanding the fine balance between protein folding and misfolding in the cell, and the large number of diseases associated with protein misfolding and aggregation.
Summary
Many aspects of the physical principles governing protein folding in vitro have been elucidated in the past decades. At the same time, a large number of cellular components involved in protein folding in vivo have been identified. But our mechanistic understanding of how these cellular components affect the energy landscape of the folding process has remained very limited, largely due to a lack of suitable methods. An opportunity to bridge this gap is single molecule fluorescence spectroscopy in combination with Förster resonance energy transfer (FRET), a new technique that allows the investigation of distance distributions and dynamics of individual protein molecules even in complex and heterogeneous environments. In a multi-disciplinary project employing methods ranging from molecular biology and protein biochemistry to optics, microfluidic mixing, and development of instrumentation and software, we plan to use single molecule spectroscopy for investigating the question how proteins find their native three-dimensional structure in a cell. Our initial focus will be on molecular chaperones, which assist protein folding in vivo, but the approach is applicable to a wide range of related phenomena and will be extended to other cellular components. This project is thus expected to nucleate a comprehensive biophysical analysis of intracellular protein folding and dynamics, eventually within live cells. A detailed investigation of these processes will be crucial for understanding the fine balance between protein folding and misfolding in the cell, and the large number of diseases associated with protein misfolding and aggregation.
Max ERC Funding
1 314 000 €
Duration
Start date: 2008-09-01, End date: 2014-08-31
