Project acronym ANGIOFAT
Project New mechanisms of angiogenesis modulators in switching between white and brown adipose tissues
Researcher (PI) Yihai Cao
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.
Summary
Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.
Max ERC Funding
2 411 547 €
Duration
Start date: 2010-03-01, End date: 2015-02-28
Project acronym ANSR
Project Ab initio approach to nuclear structure and reactions (++)
Researcher (PI) Christian Erik Forssen
Host Institution (HI) CHALMERS TEKNISKA HOEGSKOLA AB
Country Sweden
Call Details Starting Grant (StG), PE2, ERC-2009-StG
Summary Today, much interest in several fields of physics is devoted to the study of small, open quantum systems, whose properties are profoundly affected by the environment; i.e., the continuum of decay channels. In nuclear physics, these problems were originally studied in the context of nuclear reactions but their importance has been reestablished with the advent of radioactive-beam physics and the resulting interest in exotic nuclei. In particular, strong theory initiatives in this area of research will be instrumental for the success of the experimental program at the Facility for Antiproton and Ion Research (FAIR) in Germany. In addition, many of the aspects of open quantum systems are also being explored in the rapidly evolving research on ultracold atomic gases, quantum dots, and other nanodevices. A first-principles description of open quantum systems presents a substantial theoretical and computational challenge. However, the current availability of enormous computing power has allowed theorists to make spectacular progress on problems that were previously thought intractable. The importance of computational methods to study quantum many-body systems is stressed in this proposal. Our approach is based on the ab initio no-core shell model (NCSM), which is a well-established theoretical framework aimed originally at an exact description of nuclear structure starting from realistic inter-nucleon forces. A successful completion of this project requires extensions of the NCSM mathematical framework and the development of highly advanced computer codes. The '++' in the project title indicates the interdisciplinary aspects of the present research proposal and the ambition to make a significant impact on connected fields of many-body physics.
Summary
Today, much interest in several fields of physics is devoted to the study of small, open quantum systems, whose properties are profoundly affected by the environment; i.e., the continuum of decay channels. In nuclear physics, these problems were originally studied in the context of nuclear reactions but their importance has been reestablished with the advent of radioactive-beam physics and the resulting interest in exotic nuclei. In particular, strong theory initiatives in this area of research will be instrumental for the success of the experimental program at the Facility for Antiproton and Ion Research (FAIR) in Germany. In addition, many of the aspects of open quantum systems are also being explored in the rapidly evolving research on ultracold atomic gases, quantum dots, and other nanodevices. A first-principles description of open quantum systems presents a substantial theoretical and computational challenge. However, the current availability of enormous computing power has allowed theorists to make spectacular progress on problems that were previously thought intractable. The importance of computational methods to study quantum many-body systems is stressed in this proposal. Our approach is based on the ab initio no-core shell model (NCSM), which is a well-established theoretical framework aimed originally at an exact description of nuclear structure starting from realistic inter-nucleon forces. A successful completion of this project requires extensions of the NCSM mathematical framework and the development of highly advanced computer codes. The '++' in the project title indicates the interdisciplinary aspects of the present research proposal and the ambition to make a significant impact on connected fields of many-body physics.
Max ERC Funding
1 304 800 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym BARRAGE
Project Cell compartmentalization, individuation and diversity
Researcher (PI) Yves Barral
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Advanced Grant (AdG), LS3, ERC-2009-AdG
Summary Asymmetric cell division is a key mechanism for the generation of cell diversity in eukaryotes. During this process, a polarized mother cell divides into non-equivalent daughters. These may differentially inherit fate determinants, irreparable damages or age determinants. Our aim is to decipher the mechanisms governing the individualization of daughters from each other. In the past ten years, our studies identified several lateral diffusion barriers located in the plasma membrane and the endoplasmic reticulum of budding yeast. These barriers all restrict molecular exchanges between the mother cell and its bud, and thereby compartmentalize the cell already long before its division. They play key roles in the asymmetric segregation of various factors. On one side, they help maintain polarized factors into the bud. Thereby, they reinforce cell polarity and sequester daughter-specific fate determinants into the bud. On the other side they prevent aging factors of the mother from entering the bud. Hence, they play key roles in the rejuvenation of the bud, in the aging of the mother, and in the differentiation of mother and daughter from each other. Recently, we accumulated evidence that some of these barriers are subject to regulation, such as to help modulate the longevity of the mother cell in response to environmental signals. Our data also suggest that barriers help the mother cell keep traces of its life history, thereby contributing to its individuation and adaption to the environment. In this project, we will address the following questions: 1 How are these barriers assembled, functioning, and regulated? 2 What type of differentiation processes are they involved in? 3 Are they conserved in other eukaryotes, and what are their functions outside of budding yeast? These studies will shed light into the principles underlying and linking aging, rejuvenation and differentiation.
Summary
Asymmetric cell division is a key mechanism for the generation of cell diversity in eukaryotes. During this process, a polarized mother cell divides into non-equivalent daughters. These may differentially inherit fate determinants, irreparable damages or age determinants. Our aim is to decipher the mechanisms governing the individualization of daughters from each other. In the past ten years, our studies identified several lateral diffusion barriers located in the plasma membrane and the endoplasmic reticulum of budding yeast. These barriers all restrict molecular exchanges between the mother cell and its bud, and thereby compartmentalize the cell already long before its division. They play key roles in the asymmetric segregation of various factors. On one side, they help maintain polarized factors into the bud. Thereby, they reinforce cell polarity and sequester daughter-specific fate determinants into the bud. On the other side they prevent aging factors of the mother from entering the bud. Hence, they play key roles in the rejuvenation of the bud, in the aging of the mother, and in the differentiation of mother and daughter from each other. Recently, we accumulated evidence that some of these barriers are subject to regulation, such as to help modulate the longevity of the mother cell in response to environmental signals. Our data also suggest that barriers help the mother cell keep traces of its life history, thereby contributing to its individuation and adaption to the environment. In this project, we will address the following questions: 1 How are these barriers assembled, functioning, and regulated? 2 What type of differentiation processes are they involved in? 3 Are they conserved in other eukaryotes, and what are their functions outside of budding yeast? These studies will shed light into the principles underlying and linking aging, rejuvenation and differentiation.
Max ERC Funding
2 200 000 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym BFTERRA
Project Biogenesis and Functions of Telomeric Repeat-containing RNA
Researcher (PI) Claus Maria Azzalin
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Starting Grant (StG), LS1, ERC-2009-StG
Summary Telomeres are heterochromatic nucleoprotein complexes located at the end of linear eukaryotic chromosomes. Contrarily to a longstanding dogma, we have recently demonstrated that mammalian telomeres are transcribed into TElomeric Repeat containing RNA (TERRA) molecules. TERRA transcripts contain telomeric RNA repeats and are produced at least in part by DNA-dependent RNA polymerase II-mediated transcription of telomeric DNA. TERRA molecules form discrete nuclear foci that co-localize with telomeric heterochromatin in both interphase and transcriptionally inactive metaphase cells. This indicates that TERRA is an integral component of telomeres and suggests that TERRA might participate in maintaining proper telomere heterochromatin. We will use a variety of biochemistry, cell biology, molecular biology and microscopy based approaches applied to cultured mammalian cells and to the yeast Schizosaccharomyces pombe, to achieve four distinct major goals: i) We will over-express or deplete TERRA in mammalian cells in order to characterize the molecular details of putative TERRA-associated functions in maintaining normal telomere structure and function; ii) We will locate TERRA promoter regions on different human chromosome ends; iii) We will generate mammalian cellular systems in which to study artificially seeded telomeres that can be transcribed in an inducible fashion; iv) We will identify physiological regulators of TERRA by analyzing it in mammalian cultured cells where the functions of candidate factors are compromised. In parallel, taking advantage of the recent discovery of TERRA also in fission yeast, we will systematically analyze TERRA levels in fission yeast mutants derived from a complete gene knockout collection. The study of TERRA regulation and function at chromosome ends will strongly contribute to our understanding of how telomeres are maintained and will help to clarify the general functions of mammalian non-coding RNAs.
Summary
Telomeres are heterochromatic nucleoprotein complexes located at the end of linear eukaryotic chromosomes. Contrarily to a longstanding dogma, we have recently demonstrated that mammalian telomeres are transcribed into TElomeric Repeat containing RNA (TERRA) molecules. TERRA transcripts contain telomeric RNA repeats and are produced at least in part by DNA-dependent RNA polymerase II-mediated transcription of telomeric DNA. TERRA molecules form discrete nuclear foci that co-localize with telomeric heterochromatin in both interphase and transcriptionally inactive metaphase cells. This indicates that TERRA is an integral component of telomeres and suggests that TERRA might participate in maintaining proper telomere heterochromatin. We will use a variety of biochemistry, cell biology, molecular biology and microscopy based approaches applied to cultured mammalian cells and to the yeast Schizosaccharomyces pombe, to achieve four distinct major goals: i) We will over-express or deplete TERRA in mammalian cells in order to characterize the molecular details of putative TERRA-associated functions in maintaining normal telomere structure and function; ii) We will locate TERRA promoter regions on different human chromosome ends; iii) We will generate mammalian cellular systems in which to study artificially seeded telomeres that can be transcribed in an inducible fashion; iv) We will identify physiological regulators of TERRA by analyzing it in mammalian cultured cells where the functions of candidate factors are compromised. In parallel, taking advantage of the recent discovery of TERRA also in fission yeast, we will systematically analyze TERRA levels in fission yeast mutants derived from a complete gene knockout collection. The study of TERRA regulation and function at chromosome ends will strongly contribute to our understanding of how telomeres are maintained and will help to clarify the general functions of mammalian non-coding RNAs.
Max ERC Funding
1 602 600 €
Duration
Start date: 2009-10-01, End date: 2014-09-30
Project acronym BIOCARB
Project Carbonate Biomineralization in the Marine Environment: Paleo-climate proxies and the origin of vital effects
Researcher (PI) Anders Meibom
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), PE10, ERC-2009-AdG
Summary This interdisciplinary proposal has the objective to greatly enhance our understanding of fundamental biomineralization processes involved in the formation of calcium carbonates by marine organisms, such as corals, foraminifera and bivalves, in order to better understand vital effects. This is essential to the application of these carbonates as proxies for global (paleo-) environmental change. The core of the proposal is an experimental capability that I have pioneered during 2008: Dynamic stable isotopic labeling during formation of carbonate skeletons, tests, and shells, combined with NanoSIMS imaging. The NanoSIMS ion microprobe is a state-of-the-art analytical technology that allows precise elemental and isotopic imaging with a spatial resolution of ~100 nanometers. NanoSIMS imaging of the isotopic label(s) in the resulting biocarbonates and in associated cell-structures will be used to uncover cellular-level transport processes, timescales of formation of different biocarbonate components, as well as trace-elemental and isotopic fractionations. This will uncover the origin of vital effects. With this proposal, I establish a new scientific frontier and guarantee European leadership. The technical and scientific developments resulting from this work are broadly applicable and will radically change scientific ideas about marine carbonate biomineralization and compositional vital effects.
Summary
This interdisciplinary proposal has the objective to greatly enhance our understanding of fundamental biomineralization processes involved in the formation of calcium carbonates by marine organisms, such as corals, foraminifera and bivalves, in order to better understand vital effects. This is essential to the application of these carbonates as proxies for global (paleo-) environmental change. The core of the proposal is an experimental capability that I have pioneered during 2008: Dynamic stable isotopic labeling during formation of carbonate skeletons, tests, and shells, combined with NanoSIMS imaging. The NanoSIMS ion microprobe is a state-of-the-art analytical technology that allows precise elemental and isotopic imaging with a spatial resolution of ~100 nanometers. NanoSIMS imaging of the isotopic label(s) in the resulting biocarbonates and in associated cell-structures will be used to uncover cellular-level transport processes, timescales of formation of different biocarbonate components, as well as trace-elemental and isotopic fractionations. This will uncover the origin of vital effects. With this proposal, I establish a new scientific frontier and guarantee European leadership. The technical and scientific developments resulting from this work are broadly applicable and will radically change scientific ideas about marine carbonate biomineralization and compositional vital effects.
Max ERC Funding
2 182 000 €
Duration
Start date: 2010-07-01, End date: 2015-06-30
Project acronym CORALWARM
Project Corals and global warming: The Mediterranean versus the Red Sea
Researcher (PI) Zvy Dubinsky
Host Institution (HI) BAR ILAN UNIVERSITY
Country Israel
Call Details Advanced Grant (AdG), LS8, ERC-2009-AdG
Summary CoralWarm will generate for the first time projections of temperate and subtropical coral survival by integrating sublethal temperature increase effects on metabolic and skeletal processes in Mediterranean and Red Sea key species. CoralWarm unique approach is from the nano- to the macro-scale, correlating molecular events to environmental processes. This will show new pathways to future investigations on cellular mechanisms linking environmental factors to final phenotype, potentially improving prediction powers and paleoclimatological interpretation. Biological and chemical expertise will merge, producing new interdisciplinary approaches for ecophysiology and biomineralization. Field transplantations will be combined with controlled experiments under IPCC scenarios. Corals will be grown in aquaria, exposing the Mediterranean species native to cooler waters to higher temperatures, and the Red Sea ones to gradually increasing above ambient warming seawater. Virtually all state-of-the-art methods will be used, by uniquely combining the investigators expertise. Expected results include responses of algal symbionts photosynthesis, host, symbiont and holobiont respiration, biomineralization rates and patterns, including colony architecture, and reproduction to temperature and pH gradients and combinations. Integration of molecular aspects of potential replacement of symbiont clades, changes in skeletal crystallography, with biochemical and physiological aspects of temperature response, will lead to a novel mechanistic model predicting changes in coral ecology and survival prospect. High-temperature tolerant clades and species will be revealed, allowing future bioremediation actions and establishment of coral refuges, saving corals and coral reefs for future generations.
Summary
CoralWarm will generate for the first time projections of temperate and subtropical coral survival by integrating sublethal temperature increase effects on metabolic and skeletal processes in Mediterranean and Red Sea key species. CoralWarm unique approach is from the nano- to the macro-scale, correlating molecular events to environmental processes. This will show new pathways to future investigations on cellular mechanisms linking environmental factors to final phenotype, potentially improving prediction powers and paleoclimatological interpretation. Biological and chemical expertise will merge, producing new interdisciplinary approaches for ecophysiology and biomineralization. Field transplantations will be combined with controlled experiments under IPCC scenarios. Corals will be grown in aquaria, exposing the Mediterranean species native to cooler waters to higher temperatures, and the Red Sea ones to gradually increasing above ambient warming seawater. Virtually all state-of-the-art methods will be used, by uniquely combining the investigators expertise. Expected results include responses of algal symbionts photosynthesis, host, symbiont and holobiont respiration, biomineralization rates and patterns, including colony architecture, and reproduction to temperature and pH gradients and combinations. Integration of molecular aspects of potential replacement of symbiont clades, changes in skeletal crystallography, with biochemical and physiological aspects of temperature response, will lead to a novel mechanistic model predicting changes in coral ecology and survival prospect. High-temperature tolerant clades and species will be revealed, allowing future bioremediation actions and establishment of coral refuges, saving corals and coral reefs for future generations.
Max ERC Funding
3 332 032 €
Duration
Start date: 2010-06-01, End date: 2016-05-31
Project acronym DALDECS
Project Development and Application of Laser Diagnostic Techniques for Combustion Studies
Researcher (PI) Lars Eric Marcus Alden
Host Institution (HI) MAX IV Laboratory, Lund University
Country Sweden
Call Details Advanced Grant (AdG), PE8, ERC-2009-AdG
Summary This project is directed towards development of new laser diagnostic techniques and a deepened physical understanding of more established techniques, aiming at new insights in phenomena related to combustion processes. These non-intrusive techniques with high resolution in space and time, will be used for measurements of key parameters, species concentrations and temperatures. The techniques to be used are; Non-linear optical techniques, mainly Polarization spectroscopy, PS. PS will mainly be developed for sensitive detection with high spatial resolution of "new" species in the IR region, e.g. individual hydrocarbons, toxic species as well as alkali metal compounds. Multiplex measurements of these species and temperature will be developed as well as 2D visualization. Quantitative measurements with high precision and accuracy; Laser induced fluorescence and Rayleigh/Raman scattering will be developed for quantitative measurements of species concentration and 2D temperatures. Also a new technique will be developed for single ended experiments based on picosecond LIDAR. Advanced imaging techniques; New high speed (10-100 kHz) visualization techniques as well as 3D and even 4D visualization will be developed. In order to properly visualize dense sprays we will develop Ballistic Imaging as well as a new technique based on structured illumination of the area of interest for suppression of multiple scattering which normally cause blurring effects. All techniques developed above will be used for key studies of phenomena related to various combustion phenomena; turbulent combustion, multiphase conversion processes, e.g. spray combustion and gasification/pyrolysis of solid bio fuels. The techniques will also be applied for development and physical understanding of how combustion could be influenced by plasma/electrical assistance. Finally, the techniques will be prepared for applications in industrial combustion apparatus, e.g. furnaces, gasturbines and IC engines
Summary
This project is directed towards development of new laser diagnostic techniques and a deepened physical understanding of more established techniques, aiming at new insights in phenomena related to combustion processes. These non-intrusive techniques with high resolution in space and time, will be used for measurements of key parameters, species concentrations and temperatures. The techniques to be used are; Non-linear optical techniques, mainly Polarization spectroscopy, PS. PS will mainly be developed for sensitive detection with high spatial resolution of "new" species in the IR region, e.g. individual hydrocarbons, toxic species as well as alkali metal compounds. Multiplex measurements of these species and temperature will be developed as well as 2D visualization. Quantitative measurements with high precision and accuracy; Laser induced fluorescence and Rayleigh/Raman scattering will be developed for quantitative measurements of species concentration and 2D temperatures. Also a new technique will be developed for single ended experiments based on picosecond LIDAR. Advanced imaging techniques; New high speed (10-100 kHz) visualization techniques as well as 3D and even 4D visualization will be developed. In order to properly visualize dense sprays we will develop Ballistic Imaging as well as a new technique based on structured illumination of the area of interest for suppression of multiple scattering which normally cause blurring effects. All techniques developed above will be used for key studies of phenomena related to various combustion phenomena; turbulent combustion, multiphase conversion processes, e.g. spray combustion and gasification/pyrolysis of solid bio fuels. The techniques will also be applied for development and physical understanding of how combustion could be influenced by plasma/electrical assistance. Finally, the techniques will be prepared for applications in industrial combustion apparatus, e.g. furnaces, gasturbines and IC engines
Max ERC Funding
2 466 000 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym DCENSY
Project Doping, Charge Transfer and Energy Flow in Hybrid Nanoparticle Systems
Researcher (PI) Uri Banin
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Advanced Grant (AdG), PE4, ERC-2009-AdG
Summary We target a frontier in nanocrystal science of combining disparate materials into a single hybrid nanosystem. This offers an intriguing route to engineer nanomaterials with multiple functionalities in ways that are not accessible in bulk materials or in molecules. Such control of novel material combinations on a single nanoparticle or in a super-structure of assembled nanoparticles, presents alongside with the synthesis challenges, fundamental questions concerning the physical attributes of nanoscale systems. My goals are to create new highly controlled hybrid nanoparticle systems, focusing on combinations of semiconductors and metals, and to decipher the fundamental principles governing doping in nanoparticles and charge and energy transfer processes among components of the hybrid systems. The research addresses several key challenges: First, in synthesis, combining disparate material components into one hybrid nanoparticle system. Second, in self assembly, organizing a combination of semiconductor (SC) and metal nanoparticle building blocks into hybrid systems with controlled architecture. Third in fundamental physico-chemical questions pertaining to the unique attributes of the hybrid systems, constituting a key component of the research. A first aspect concerns doping of SC nanoparticles with metal atoms. A second aspect concerns light-induced charge transfer between the SC part and metal parts of the hybrid constructs. A third related aspect concerns energy transfer processes between the SC and metal components and the interplay between near-field enhancement and fluorescence quenching effects. Due to the new properties, significant impact on nanocrystal applications in solar energy harvesting, biological tagging, sensing, optics and electropotics is expected.
Summary
We target a frontier in nanocrystal science of combining disparate materials into a single hybrid nanosystem. This offers an intriguing route to engineer nanomaterials with multiple functionalities in ways that are not accessible in bulk materials or in molecules. Such control of novel material combinations on a single nanoparticle or in a super-structure of assembled nanoparticles, presents alongside with the synthesis challenges, fundamental questions concerning the physical attributes of nanoscale systems. My goals are to create new highly controlled hybrid nanoparticle systems, focusing on combinations of semiconductors and metals, and to decipher the fundamental principles governing doping in nanoparticles and charge and energy transfer processes among components of the hybrid systems. The research addresses several key challenges: First, in synthesis, combining disparate material components into one hybrid nanoparticle system. Second, in self assembly, organizing a combination of semiconductor (SC) and metal nanoparticle building blocks into hybrid systems with controlled architecture. Third in fundamental physico-chemical questions pertaining to the unique attributes of the hybrid systems, constituting a key component of the research. A first aspect concerns doping of SC nanoparticles with metal atoms. A second aspect concerns light-induced charge transfer between the SC part and metal parts of the hybrid constructs. A third related aspect concerns energy transfer processes between the SC and metal components and the interplay between near-field enhancement and fluorescence quenching effects. Due to the new properties, significant impact on nanocrystal applications in solar energy harvesting, biological tagging, sensing, optics and electropotics is expected.
Max ERC Funding
2 499 000 €
Duration
Start date: 2010-06-01, End date: 2015-05-31
Project acronym DEPICT
Project Design principles and controllability of protein circuits
Researcher (PI) Uri Alon
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Advanced Grant (AdG), LS2, ERC-2009-AdG
Summary Cells use circuits of interacting proteins to respond to their environment. In the past decades, molecular biology has provided detailed knowledge on the proteins in these circuits and their interactions. To fully understand circuit function requires, in addition to molecular knowledge, new concepts that explain how multiple components work together to perform systems level functions. Our lab has been a leader in defining such concepts, based on combined experimental and theoretical study of well characterized circuits in bacteria and human cells. In this proposal we aim to find novel principles on how circuits resist fluctuations and errors, and how they can be controlled by drugs: (1) Why do key regulatory systems use bifunctional enzymes that catalyze antagonistic reactions (e.g. both kinase and phosphatase)? We will test the role of bifunctional enzymes in making circuits robust to variations in protein levels. (2) Why are some genes regulated by a repressor and others by an activator? We will test this in the context of reduction of errors in transcription control. (3) Are there principles that describe how drugs combine to affect protein dynamics in human cells? We will use a novel dynamic proteomics approach developed in our lab to explore how protein dynamics can be controlled by drug combinations. This research will define principles that unite our understanding of seemingly distinct biological systems, and explain their particular design in terms of systems-level functions. This understanding will help form the basis for a future medicine that rationally controls the state of the cell based on a detailed blueprint of their circuit design, and quantitative principles for the effects of drugs on this circuitry.
Summary
Cells use circuits of interacting proteins to respond to their environment. In the past decades, molecular biology has provided detailed knowledge on the proteins in these circuits and their interactions. To fully understand circuit function requires, in addition to molecular knowledge, new concepts that explain how multiple components work together to perform systems level functions. Our lab has been a leader in defining such concepts, based on combined experimental and theoretical study of well characterized circuits in bacteria and human cells. In this proposal we aim to find novel principles on how circuits resist fluctuations and errors, and how they can be controlled by drugs: (1) Why do key regulatory systems use bifunctional enzymes that catalyze antagonistic reactions (e.g. both kinase and phosphatase)? We will test the role of bifunctional enzymes in making circuits robust to variations in protein levels. (2) Why are some genes regulated by a repressor and others by an activator? We will test this in the context of reduction of errors in transcription control. (3) Are there principles that describe how drugs combine to affect protein dynamics in human cells? We will use a novel dynamic proteomics approach developed in our lab to explore how protein dynamics can be controlled by drug combinations. This research will define principles that unite our understanding of seemingly distinct biological systems, and explain their particular design in terms of systems-level functions. This understanding will help form the basis for a future medicine that rationally controls the state of the cell based on a detailed blueprint of their circuit design, and quantitative principles for the effects of drugs on this circuitry.
Max ERC Funding
2 261 440 €
Duration
Start date: 2010-03-01, End date: 2015-02-28
Project acronym DHISP
Project Dorsal Horn Interneurons in Sensory Processing
Researcher (PI) Hanns Ulrich Zeilhofer
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary Chronic pain syndromes are to a large extent due to maladaptive plastic changes in the CNS. A CNS area particularly relevant for such changes is the spinal dorsal horn, where inputs from nociceptive and non-nociceptive fibers undergo their first synaptic integration. This area harbors a sophisticated network of interneurons, which function as a gate-control unit for incoming sensory signals. Several different types of interneurons can be distinguished based e.g. on their neurotransmitter and neuropeptide content. Despite more than 40 years of research, our knowledge about the integration of these neurons in dorsal horn circuits and their contribution to sensory processing is still very limited. This proposal aims at a comprehensive characterization of the dorsal horn neuronal network under normal conditions and in chronic pain states with a focus on inhibitory interneurons. A genome-wide analysis of the gene expression profile shall be made from defined dorsal horn interneurons genetically tagged with fluorescent markers and isolated by fluorescence activated cell sorting. A functional characterization of the connectivity of these neurons in spinal cord slices and of their role in in vivo sensory processing shall be achieved with optogenetic tools (channelrhodopsin-2), which permit activation of these neurons with light. Finally, behavioral analyses shall be made in mice after diphteria toxin-mediated ablation of defined interneuron types. All three approaches shall be applied to naïve mice and to mice with inflammatory or neuropathic pain. The results from these studies will improve our understanding of the malfunctioning of sensory processing in chronic pain states and will provide the basis for novel approaches to the prevention or reversal of chronic pain states.
Summary
Chronic pain syndromes are to a large extent due to maladaptive plastic changes in the CNS. A CNS area particularly relevant for such changes is the spinal dorsal horn, where inputs from nociceptive and non-nociceptive fibers undergo their first synaptic integration. This area harbors a sophisticated network of interneurons, which function as a gate-control unit for incoming sensory signals. Several different types of interneurons can be distinguished based e.g. on their neurotransmitter and neuropeptide content. Despite more than 40 years of research, our knowledge about the integration of these neurons in dorsal horn circuits and their contribution to sensory processing is still very limited. This proposal aims at a comprehensive characterization of the dorsal horn neuronal network under normal conditions and in chronic pain states with a focus on inhibitory interneurons. A genome-wide analysis of the gene expression profile shall be made from defined dorsal horn interneurons genetically tagged with fluorescent markers and isolated by fluorescence activated cell sorting. A functional characterization of the connectivity of these neurons in spinal cord slices and of their role in in vivo sensory processing shall be achieved with optogenetic tools (channelrhodopsin-2), which permit activation of these neurons with light. Finally, behavioral analyses shall be made in mice after diphteria toxin-mediated ablation of defined interneuron types. All three approaches shall be applied to naïve mice and to mice with inflammatory or neuropathic pain. The results from these studies will improve our understanding of the malfunctioning of sensory processing in chronic pain states and will provide the basis for novel approaches to the prevention or reversal of chronic pain states.
Max ERC Funding
2 467 000 €
Duration
Start date: 2010-05-01, End date: 2016-04-30
Project acronym DYNALLO
Project Towards a Dynamical Understanding of Allostery
Researcher (PI) Peter Hamm
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Advanced Grant (AdG), PE4, ERC-2009-AdG
Summary Allostery is a fundamental concept Nature uses to regulate the affinity of a certain substrate to an active site of a protein by binding a ligand to a distant allosteric site. We will design experimental tools to gain an atomistic understanding of the conformational transitions that give rise to allostery. We will approach the problem from two distinctively different directions. First, we will initiate conformational transitions of proteins that per se are not photoswitchable, by cross-linking two sites of an allosteric protein with a photo-switchable azobenzene-moiety to initiate a conformational transition similar to ligand binding. We will use ultrafast infrared spectroscopy to time-resolve the conformational transition. Second, we will experimentally verify a frequently expressed hypothesis that allosteric and active site communicate by exchange of vibrational energy. To that end, we will design a versatile approach that allows us to locally deposit vibrational energy at essentially any site in a protein (e.g. through pumping of an optical chromophore that undergoes ultrafast internal conversion), and to detect its appearance at any other site by using vibrational transitions as local thermometers. Thereby, we will map out a network of connectivity in a given protein. Both approaches will applied both to one and the same protein family. One concrete example are PDZ domains, which are among the smallest allosteric proteins, and for which the connection between allostery and vibrational energy flow has been made explicit, based on computer simulations. We will eventually test this hypothesis experimentally, and provide the foundation for a description of allostery that is on an equal footing as our current understanding of protein folding.
Summary
Allostery is a fundamental concept Nature uses to regulate the affinity of a certain substrate to an active site of a protein by binding a ligand to a distant allosteric site. We will design experimental tools to gain an atomistic understanding of the conformational transitions that give rise to allostery. We will approach the problem from two distinctively different directions. First, we will initiate conformational transitions of proteins that per se are not photoswitchable, by cross-linking two sites of an allosteric protein with a photo-switchable azobenzene-moiety to initiate a conformational transition similar to ligand binding. We will use ultrafast infrared spectroscopy to time-resolve the conformational transition. Second, we will experimentally verify a frequently expressed hypothesis that allosteric and active site communicate by exchange of vibrational energy. To that end, we will design a versatile approach that allows us to locally deposit vibrational energy at essentially any site in a protein (e.g. through pumping of an optical chromophore that undergoes ultrafast internal conversion), and to detect its appearance at any other site by using vibrational transitions as local thermometers. Thereby, we will map out a network of connectivity in a given protein. Both approaches will applied both to one and the same protein family. One concrete example are PDZ domains, which are among the smallest allosteric proteins, and for which the connection between allostery and vibrational energy flow has been made explicit, based on computer simulations. We will eventually test this hypothesis experimentally, and provide the foundation for a description of allostery that is on an equal footing as our current understanding of protein folding.
Max ERC Funding
2 400 000 €
Duration
Start date: 2010-02-01, End date: 2015-07-31
Project acronym ELECSPECIONS
Project Electronic spectra of cold, large interstellar ions
Researcher (PI) John Paul Maier
Host Institution (HI) UNIVERSITAT BASEL
Country Switzerland
Call Details Advanced Grant (AdG), PE4, ERC-2009-AdG
Summary The purpose of this project is to measure for the first time gas-phase spectra of large carbon containing cations, at low temperatures, which are of astrophysical importance. Knowledge of electronic spectroscopy of such molecules is also of pertinence in a number of areas of chemistry and physics, enabling their identification in planetary atmospheres, flames and plasmas and as intermediates in chemical reaction dynamics. This project is interdisciplinary, bridging the areas of chemistry, physics, and astrophysics. It encompasses state of the art techniques of chemical physics and aims at obtaining information to solve the long standing enigma in observational astronomy, the identification of some of the molecules causing absorption of starlight in diffuse interstellar clouds. The project uses ion trapping technology, whereby mass-selected species are held in a radio-frequency field and the vibrations and rotations are relaxed by collisions with cold helium to typical interstellar temperatures of 10-30 K. The electronic spectra of a number of cations, selected on the basis of their special properties including those of bare carbon chains, rings and fullerenes, polycyclic aromatic hydrocarbon cations and their protonated forms will be measured using new detection schemes. The first approach is based on photo-induced charge transfer which is turned on upon laser excitation and the second uses the possibility of rare-gas complexation in the ground but not excited state.
Summary
The purpose of this project is to measure for the first time gas-phase spectra of large carbon containing cations, at low temperatures, which are of astrophysical importance. Knowledge of electronic spectroscopy of such molecules is also of pertinence in a number of areas of chemistry and physics, enabling their identification in planetary atmospheres, flames and plasmas and as intermediates in chemical reaction dynamics. This project is interdisciplinary, bridging the areas of chemistry, physics, and astrophysics. It encompasses state of the art techniques of chemical physics and aims at obtaining information to solve the long standing enigma in observational astronomy, the identification of some of the molecules causing absorption of starlight in diffuse interstellar clouds. The project uses ion trapping technology, whereby mass-selected species are held in a radio-frequency field and the vibrations and rotations are relaxed by collisions with cold helium to typical interstellar temperatures of 10-30 K. The electronic spectra of a number of cations, selected on the basis of their special properties including those of bare carbon chains, rings and fullerenes, polycyclic aromatic hydrocarbon cations and their protonated forms will be measured using new detection schemes. The first approach is based on photo-induced charge transfer which is turned on upon laser excitation and the second uses the possibility of rare-gas complexation in the ground but not excited state.
Max ERC Funding
1 898 624 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym ERGODICNONCOMPACT
Project Ergodic theory on non compact spaces
Researcher (PI) Omri Moshe Sarig
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Starting Grant (StG), PE1, ERC-2009-StG
Summary The proposal is to look for, and investigate, new ergodic theoretic types of behavior for dynamical systems which act on non compact spaces. These could include transience and non-trivial ways of escape to infinity, critical phenomena similar to phase transitions, and new types of measure rigidity. There are potential applications to smooth ergodic theory (non-uniform hyperbolicity), algebraic ergodic theory (actions on homogeneous spaces), and probability theory (weakly dependent stochastic processes).
Summary
The proposal is to look for, and investigate, new ergodic theoretic types of behavior for dynamical systems which act on non compact spaces. These could include transience and non-trivial ways of escape to infinity, critical phenomena similar to phase transitions, and new types of measure rigidity. There are potential applications to smooth ergodic theory (non-uniform hyperbolicity), algebraic ergodic theory (actions on homogeneous spaces), and probability theory (weakly dependent stochastic processes).
Max ERC Funding
539 479 €
Duration
Start date: 2009-10-01, End date: 2014-09-30
Project acronym ESEI
Project Engineering Social and Economic Institutions
Researcher (PI) Jacob Goeree
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Advanced Grant (AdG), SH1, ERC-2009-AdG
Summary The advent of the Internet and the increased power of modern day computing have dramatically changed the economic landscape. Billions of dollars worth of goods are being auctioned among geographically dispersed buyers; online brokerages are used to find jobs, trade stocks, make travel arrangements, etc. The architecture of these online (trading) platforms is typically rooted in their pre-Internet counterparts, and advances in the theory of market design combined with increased computing capabilities prompt a careful re-evaluation. This proposal concerns the creation of novel, more flexible institutions using an approach that combines theory, laboratory experiments, and practical policy. The first project enhances our understanding of newly designed package auctions by developing equilibrium models of competitive bidding and measuring the efficacy of alternative formats in controlled experiments. The next project studies novel market forms that allow for all-or-nothing trades to alleviate inefficiencies and enhance dynamic stability when complementarities exist. The third project concerns the design of market regulation and procurement contests to create better incentives for research and development. The fourth project addresses information aggregation properties of alternative voting institutions, suggesting improvements for referenda and jury/committee voting. The Internet has also dramatically altered the nature of social interactions. Emerging institutions such as online social networking tools, rating systems, and web-community Q&A services reduce social distances and catalyze opportunities for social learning. The final project focuses on social learning in a variety of settings and on the impact of social networks on behavior. Combined these projects generate insights that apply to a broad array of social and economic environments and that will guide practitioners to the use of better designed institutions.
Summary
The advent of the Internet and the increased power of modern day computing have dramatically changed the economic landscape. Billions of dollars worth of goods are being auctioned among geographically dispersed buyers; online brokerages are used to find jobs, trade stocks, make travel arrangements, etc. The architecture of these online (trading) platforms is typically rooted in their pre-Internet counterparts, and advances in the theory of market design combined with increased computing capabilities prompt a careful re-evaluation. This proposal concerns the creation of novel, more flexible institutions using an approach that combines theory, laboratory experiments, and practical policy. The first project enhances our understanding of newly designed package auctions by developing equilibrium models of competitive bidding and measuring the efficacy of alternative formats in controlled experiments. The next project studies novel market forms that allow for all-or-nothing trades to alleviate inefficiencies and enhance dynamic stability when complementarities exist. The third project concerns the design of market regulation and procurement contests to create better incentives for research and development. The fourth project addresses information aggregation properties of alternative voting institutions, suggesting improvements for referenda and jury/committee voting. The Internet has also dramatically altered the nature of social interactions. Emerging institutions such as online social networking tools, rating systems, and web-community Q&A services reduce social distances and catalyze opportunities for social learning. The final project focuses on social learning in a variety of settings and on the impact of social networks on behavior. Combined these projects generate insights that apply to a broad array of social and economic environments and that will guide practitioners to the use of better designed institutions.
Max ERC Funding
1 797 525 €
Duration
Start date: 2010-01-01, End date: 2015-12-31
Project acronym EUKARYOTIC RIBOSOME
Project Structural studies of the eukaryotic ribosome by X-ray crystallography
Researcher (PI) Nenad Ban
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Advanced Grant (AdG), LS1, ERC-2009-AdG
Summary The ribosome is a large cellular organelle that plays a central role in the process of protein synthesis in all organisms. Currently, structural information at atomic resolution exists only for bacterial ribosomes and some of their functional complexes. Eukaryotic ribosomes are larger and significantly more complex than their bacterial counterparts. They consist of two unequal subunits with a combined molecular weight of approximately 4 million Daltons and contain 70-80 different protein molecules and four different RNAs. Currently the only structural information on eukaryotic ribosomes is available from cryo electron microscopic reconstructions in the nanometer resolution range, which is insufficient to derive information about the function of the eukaryotic ribosome at the atomic level. The aim of this proposal is to use X-ray crystallography to obtain structural and functional information on the eukaryotic ribosome and its functional complexes at high resolution. The key targets of the structural work will be: i) the structure of the small ribosomal subunit, ii) the structure of the large ribosomal subunit, and iii) structures of complexes involved in the initiation of protein synthesis. Besides the obvious fundamental importance of this research for understanding protein synthesis in eukaryotes the proposed studies will also be the prerequisite for understanding the structural basis of the regulation of protein synthesis in normal cells and how it is perturbed in various diseases. Finally, comparing the structures of bacterial and eukaryotic ribosomes is important for understanding the specificity of various clinically used antibiotics for the bacterial ribosome.
Summary
The ribosome is a large cellular organelle that plays a central role in the process of protein synthesis in all organisms. Currently, structural information at atomic resolution exists only for bacterial ribosomes and some of their functional complexes. Eukaryotic ribosomes are larger and significantly more complex than their bacterial counterparts. They consist of two unequal subunits with a combined molecular weight of approximately 4 million Daltons and contain 70-80 different protein molecules and four different RNAs. Currently the only structural information on eukaryotic ribosomes is available from cryo electron microscopic reconstructions in the nanometer resolution range, which is insufficient to derive information about the function of the eukaryotic ribosome at the atomic level. The aim of this proposal is to use X-ray crystallography to obtain structural and functional information on the eukaryotic ribosome and its functional complexes at high resolution. The key targets of the structural work will be: i) the structure of the small ribosomal subunit, ii) the structure of the large ribosomal subunit, and iii) structures of complexes involved in the initiation of protein synthesis. Besides the obvious fundamental importance of this research for understanding protein synthesis in eukaryotes the proposed studies will also be the prerequisite for understanding the structural basis of the regulation of protein synthesis in normal cells and how it is perturbed in various diseases. Finally, comparing the structures of bacterial and eukaryotic ribosomes is important for understanding the specificity of various clinically used antibiotics for the bacterial ribosome.
Max ERC Funding
2 446 725 €
Duration
Start date: 2010-07-01, End date: 2015-06-30
Project acronym FLAMENANOMANUFACTURE
Project Flame Aerosol Reactors for Manufacturing of Surface-Functionalized Nanoscale Materials and Devices
Researcher (PI) Sotirios Pratsinis
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Advanced Grant (AdG), PE8, ERC-2009-AdG
Summary Nanotechnology research has been directed mostly to the design and synthesis of (a) materials with passive nanostructures (e.g. coatings, nanoparticles of organics, metals and ceramics) and (b) active devices with nanostructured materials (e.g. transistors, amplifiers, sensors, actuators etc). Little is known, however, about how well the unique properties of nanostructured materials are reproduced during their large scale synthesis, and how such manufacturing can be designed and carried out. A key goal here is to fundamentally understand synthesis of surface-functionalized, nanostructured, multicomponent particles by flame aerosol reactors (a proven scalable technology for simple ceramic oxide nanopowders). That way technology for making such sophisticated materials would be developed systematically for their efficient manufacture so that active devices containing them can be made economically. Our focus is on understanding aerosol formation of layered solid or fractal-like nanostructures by developing quantitative process models and systematic comparison to experimental data. This understanding will be used to guide synthesis of challenging nanoparticle compositions and process scale-up with close attention to safe product handling and health effects. The ultimate goal of this research is to address the next frontier of this field, namely the assembling of high performance active devices made with such functionalized or layered nanoparticles. Here these devices include but not limited to (a) actuators containing layered single superparamagnetic nanoparticles and (b) ultraselective and highly sensitive sensors made with highly conductive but disperse nanoelectrode layers for detection of trace organic vapors in the human breath for early diagnosis of serious illnesses.
Summary
Nanotechnology research has been directed mostly to the design and synthesis of (a) materials with passive nanostructures (e.g. coatings, nanoparticles of organics, metals and ceramics) and (b) active devices with nanostructured materials (e.g. transistors, amplifiers, sensors, actuators etc). Little is known, however, about how well the unique properties of nanostructured materials are reproduced during their large scale synthesis, and how such manufacturing can be designed and carried out. A key goal here is to fundamentally understand synthesis of surface-functionalized, nanostructured, multicomponent particles by flame aerosol reactors (a proven scalable technology for simple ceramic oxide nanopowders). That way technology for making such sophisticated materials would be developed systematically for their efficient manufacture so that active devices containing them can be made economically. Our focus is on understanding aerosol formation of layered solid or fractal-like nanostructures by developing quantitative process models and systematic comparison to experimental data. This understanding will be used to guide synthesis of challenging nanoparticle compositions and process scale-up with close attention to safe product handling and health effects. The ultimate goal of this research is to address the next frontier of this field, namely the assembling of high performance active devices made with such functionalized or layered nanoparticles. Here these devices include but not limited to (a) actuators containing layered single superparamagnetic nanoparticles and (b) ultraselective and highly sensitive sensors made with highly conductive but disperse nanoelectrode layers for detection of trace organic vapors in the human breath for early diagnosis of serious illnesses.
Max ERC Funding
2 500 000 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym GAME-DYNAMICS
Project Game Theory: Dynamic Approaches
Researcher (PI) Sergiu Hart
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Advanced Grant (AdG), SH1, ERC-2009-AdG
Summary The general framework is that of game theory, with multiple participants ( players ) that interact repeatedly over time. The players may be people, corporations, nations, computers even genes. While many of the standard concepts of game theory are static by their very nature (for example, strategic equilibria and cooperative solutions), it is of utmost importance theoretically as well as in applications to study dynamic processes, and relate them to appropriate static solutions. This is a fundamental issue. On the one hand, the significance of a solution depends in particular on how easy it is to reach it. On the other hand, natural dynamics, that is, processes that to a certain degree reflect observed behaviors and actual institutions, are important to study and understand in their own right. We propose to work on three main areas. First, adaptive dynamics: the goal is to characterize those classes of dynamics for which convergence to Nash or correlated equilibria can be obtained, and those for which it cannot, and to find and study natural dynamics that are related to actual behavior and yield useful insights. Second, evolutionary dynamics: the goal is to investigate evolutionary and similar dynamics, with a particular emphasis on understanding the role that large populations may play, and on characterizing which equilibria are evolutionarily stable and which are not. Third, bargaining and cooperation: the goal is to develop a general research program that studies natural bargaining procedures that lead to cooperation and are based directly on the strategic form; some particular aims are to establish connections between the bargaining institutions and the resulting cooperative solutions, and to analyze relevant economic models.
Summary
The general framework is that of game theory, with multiple participants ( players ) that interact repeatedly over time. The players may be people, corporations, nations, computers even genes. While many of the standard concepts of game theory are static by their very nature (for example, strategic equilibria and cooperative solutions), it is of utmost importance theoretically as well as in applications to study dynamic processes, and relate them to appropriate static solutions. This is a fundamental issue. On the one hand, the significance of a solution depends in particular on how easy it is to reach it. On the other hand, natural dynamics, that is, processes that to a certain degree reflect observed behaviors and actual institutions, are important to study and understand in their own right. We propose to work on three main areas. First, adaptive dynamics: the goal is to characterize those classes of dynamics for which convergence to Nash or correlated equilibria can be obtained, and those for which it cannot, and to find and study natural dynamics that are related to actual behavior and yield useful insights. Second, evolutionary dynamics: the goal is to investigate evolutionary and similar dynamics, with a particular emphasis on understanding the role that large populations may play, and on characterizing which equilibria are evolutionarily stable and which are not. Third, bargaining and cooperation: the goal is to develop a general research program that studies natural bargaining procedures that lead to cooperation and are based directly on the strategic form; some particular aims are to establish connections between the bargaining institutions and the resulting cooperative solutions, and to analyze relevant economic models.
Max ERC Funding
1 361 000 €
Duration
Start date: 2010-01-01, End date: 2015-12-31
Project acronym GLC
Project Langlands correspondence and its variants
Researcher (PI) David Kazhdan
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Advanced Grant (AdG), PE1, ERC-2009-AdG
Summary Sometimes in the sciences there are different yet complementary descriptions for the same object. This extends to the particle-wave duality of quantum mechanics; one mathematical analog of this duality is the Fourier transform. Questions that are difficult when formulated in one language of science may become simple when interpreted in another. The Langlands conjecture posits the existence of a correspondence between problems in arithmetic and in Representation Theory. The Langlands conjecture has only been proven for a limited number of cases, but even this has solved problems such as the famous Fermat conjecture. The aim of this project is to continue study of the "classical" aspects of the Langlands conjecture and to extend the conjecture to the quantum geometric Langlands correspondence, higher-dimensional fields, Kac-Moody groups (with D.Gaitsgory: quantum Langlands correspondence; D.Gaitsgory and E. Hrushevsi: groups over higher-dimensional fields; A. Braverman: Kac-Moody groups; R. Bezrukavnikov, S.Debacker, Y.Varshavsky: classical aspects of the correspondence; A. Berenstein: geometric crystals and crystal bases). The quantum case is much more symmetric than the classical case and can lead in the limit q->0 to new insights into the classical case. The quantum case is also related to the multiple Dirichlet series. New results in the quantum case would lead to progress in understanding important Number Theoretic questions. Extending the Langlands correspondence to groups over higher-dimensional fields could substantially enlarge its applicability. Studying Kac-Moody groups would provide tools for the new important class of L-functions. This progress could lead to a proof of the existence of the analytic continuation of classical L-functions. The geometric Langlands correspondence is closely related to T-symmetry in 4-dimensional gauge theory and the understanding of this relation is important for both Mathematics and Physics.
Summary
Sometimes in the sciences there are different yet complementary descriptions for the same object. This extends to the particle-wave duality of quantum mechanics; one mathematical analog of this duality is the Fourier transform. Questions that are difficult when formulated in one language of science may become simple when interpreted in another. The Langlands conjecture posits the existence of a correspondence between problems in arithmetic and in Representation Theory. The Langlands conjecture has only been proven for a limited number of cases, but even this has solved problems such as the famous Fermat conjecture. The aim of this project is to continue study of the "classical" aspects of the Langlands conjecture and to extend the conjecture to the quantum geometric Langlands correspondence, higher-dimensional fields, Kac-Moody groups (with D.Gaitsgory: quantum Langlands correspondence; D.Gaitsgory and E. Hrushevsi: groups over higher-dimensional fields; A. Braverman: Kac-Moody groups; R. Bezrukavnikov, S.Debacker, Y.Varshavsky: classical aspects of the correspondence; A. Berenstein: geometric crystals and crystal bases). The quantum case is much more symmetric than the classical case and can lead in the limit q->0 to new insights into the classical case. The quantum case is also related to the multiple Dirichlet series. New results in the quantum case would lead to progress in understanding important Number Theoretic questions. Extending the Langlands correspondence to groups over higher-dimensional fields could substantially enlarge its applicability. Studying Kac-Moody groups would provide tools for the new important class of L-functions. This progress could lead to a proof of the existence of the analytic continuation of classical L-functions. The geometric Langlands correspondence is closely related to T-symmetry in 4-dimensional gauge theory and the understanding of this relation is important for both Mathematics and Physics.
Max ERC Funding
1 277 060 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym HUCNC
Project Conserved Non-Coding Sequences; function, variability and phenotypic consequences
Researcher (PI) Stylianos Antonarakis
Host Institution (HI) UNIVERSITE DE GENEVE
Country Switzerland
Call Details Advanced Grant (AdG), LS2, ERC-2009-AdG
Summary Comparative genomics revealed that ~5% of the human genome is conserved among mammals. This fraction is likely functional, and could harbor pathogenic mutations. We have shown (Nature 2002, Science 2003) that more than half of the constrained fraction of the genome consists of Conserved Non-Coding sequences (CNCs). Model organisms provided evidence for enhancer activity for a fraction of CNCs; in addition another fraction is part of large non-coding RNAs (lincRNA). However, the function of the majority of CNCs is unknown. Importantly, a few pathogenic mutations in CNCs have been associated with genetic disorders. We propose to i) perform functional analysis of CNCs, and ii) identify the spectrum of pathogenic CNC mutations in recognizable human phenotypes. The aims are: 1. Functional genomic connectivity of CNCs 1a. Use 4C in CNCs in various cell types and determine their physical genomic interactions. 1b. Perform targeted disruption of CNCs in cells and assess the functional outcomes. 2. Pathogenic variation of CNCs 2a. Assess the common variation in CNCs: i) common deletion/insertions in 350 samples by aCGH of all human CNCs; ii) common SNP/small indels using DNA selection and High Throughput Sequencing (HTS) of CNCs in 100 samples. 2b. Identify likely pathogenic mutations in developmental syndromes. Search for i) large deletions and duplications of CNCs using aCGH in 1500 samples with malformation syndromes, 1000 from spontaneous abortions, and 500 with X-linked mental retardation; and ii) point mutations in these samples by targeted HTS. The distinction between pathogenic and non-pathogenic variants is difficult, and we propose approaches to meet the challenge. 3. Genetic control (cis and trans eQTLs) of expression variation of CNC lincRNAs, using 200 samples.
Summary
Comparative genomics revealed that ~5% of the human genome is conserved among mammals. This fraction is likely functional, and could harbor pathogenic mutations. We have shown (Nature 2002, Science 2003) that more than half of the constrained fraction of the genome consists of Conserved Non-Coding sequences (CNCs). Model organisms provided evidence for enhancer activity for a fraction of CNCs; in addition another fraction is part of large non-coding RNAs (lincRNA). However, the function of the majority of CNCs is unknown. Importantly, a few pathogenic mutations in CNCs have been associated with genetic disorders. We propose to i) perform functional analysis of CNCs, and ii) identify the spectrum of pathogenic CNC mutations in recognizable human phenotypes. The aims are: 1. Functional genomic connectivity of CNCs 1a. Use 4C in CNCs in various cell types and determine their physical genomic interactions. 1b. Perform targeted disruption of CNCs in cells and assess the functional outcomes. 2. Pathogenic variation of CNCs 2a. Assess the common variation in CNCs: i) common deletion/insertions in 350 samples by aCGH of all human CNCs; ii) common SNP/small indels using DNA selection and High Throughput Sequencing (HTS) of CNCs in 100 samples. 2b. Identify likely pathogenic mutations in developmental syndromes. Search for i) large deletions and duplications of CNCs using aCGH in 1500 samples with malformation syndromes, 1000 from spontaneous abortions, and 500 with X-linked mental retardation; and ii) point mutations in these samples by targeted HTS. The distinction between pathogenic and non-pathogenic variants is difficult, and we propose approaches to meet the challenge. 3. Genetic control (cis and trans eQTLs) of expression variation of CNC lincRNAs, using 200 samples.
Max ERC Funding
2 353 920 €
Duration
Start date: 2010-07-01, End date: 2015-06-30
Project acronym HYDRATIONLUBE
Project Hydration lubrication: exploring a new paradigm
Researcher (PI) Jacob Klein
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Advanced Grant (AdG), PE4, ERC-2009-AdG
Summary In recent years, as first established in some 6 papers in Science and Nature from the PI s group, a new paradigm has emerged. This reveals the remarkable and unsuspected - role of hydration layers in modulating frictional forces between sliding surfaces or molecular layers in aqueous media, termed hydration lubrication, in which the lubricating mode is completely different from the classic one of oils or surfactants. In this project we address the substantial challenges that have now arisen: what are the underlying mechanisms controlling this effect? what are the potential breakthroughs that it may lead to? We will answer these questions through several interrelated objectives designed to address both fundamental aspects, as well as limits of applicability. We will use surface force balance (SFB) experiments, for which we will develop new methodologies, to characterize normal and frictional forces between atomically smooth surfaces where the nature of the surfaces (hydrophilic, hydrophobic, metallic, polymeric), as well as their electric potential, may be independently varied. We will examine mono- and multivalent ions to establish the role of relaxation rates and hydration energies in controlling the hydration lubrication, will probe hydration interactions at both hydrophobic/hydrophilic surfaces and will monitor slip of hydrated ions past surfaces. We will also characterize the hydration lubrication properties of a wide range of novel surface systems, including surfactants, liposomes, polymer brushes and, importantly, liposomes, using also synchrotron X-ray reflectometry for structural information. Attainment of these objectives should lead to conceptual breakthroughs both in our understanding of this new paradigm, and for its practical implications.
Summary
In recent years, as first established in some 6 papers in Science and Nature from the PI s group, a new paradigm has emerged. This reveals the remarkable and unsuspected - role of hydration layers in modulating frictional forces between sliding surfaces or molecular layers in aqueous media, termed hydration lubrication, in which the lubricating mode is completely different from the classic one of oils or surfactants. In this project we address the substantial challenges that have now arisen: what are the underlying mechanisms controlling this effect? what are the potential breakthroughs that it may lead to? We will answer these questions through several interrelated objectives designed to address both fundamental aspects, as well as limits of applicability. We will use surface force balance (SFB) experiments, for which we will develop new methodologies, to characterize normal and frictional forces between atomically smooth surfaces where the nature of the surfaces (hydrophilic, hydrophobic, metallic, polymeric), as well as their electric potential, may be independently varied. We will examine mono- and multivalent ions to establish the role of relaxation rates and hydration energies in controlling the hydration lubrication, will probe hydration interactions at both hydrophobic/hydrophilic surfaces and will monitor slip of hydrated ions past surfaces. We will also characterize the hydration lubrication properties of a wide range of novel surface systems, including surfactants, liposomes, polymer brushes and, importantly, liposomes, using also synchrotron X-ray reflectometry for structural information. Attainment of these objectives should lead to conceptual breakthroughs both in our understanding of this new paradigm, and for its practical implications.
Max ERC Funding
2 304 180 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym ID-CAB
Project Individual differences in Collective Animal Behaviour
Researcher (PI) David Sumpter
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), LS8, ERC-2009-StG
Summary One of the key challenges in scientific research is to link together our understanding of different levels of biological organisation. This challenge is fundamental to the scientific endeavour: from understand how genes interact to drive the cell, to how cells interact to form organisms, up to how organisms interact to form groups and societies. My own and the research of others has addressed this question in the context of the collective behaviour of animals. Mathematical models of complex systems have been used to successfully predict experimental outcome. Most previous studies are however limited in one important aspect: individuals are treated as identical units. The aim of the proposed research proposed is to investigate features which produce differences within the units. The model systems of our study will be sticklebacks, homing pigeons and house sparrows. Individuals can differ from each other on a range of time scales, from information acquired within the last few minutes, through socially learnt information, to genetically inherited differences. Through a series of experiments on each of the study species, the development of mathematical models which incorporate between individual differences, and novel forms of data analysis, we will begin to understand the role played by individual differences within groups. We will look at the rules of motion for fish and birds; the role of personality in decision-making and how short term information differences improve decision-making accuracy. Achieving the project objectives will greatly enhance our understanding of the relationship between individual animals and the groups they live in, as well as impacting on our understanding of individual differences in other areas of biology.
Summary
One of the key challenges in scientific research is to link together our understanding of different levels of biological organisation. This challenge is fundamental to the scientific endeavour: from understand how genes interact to drive the cell, to how cells interact to form organisms, up to how organisms interact to form groups and societies. My own and the research of others has addressed this question in the context of the collective behaviour of animals. Mathematical models of complex systems have been used to successfully predict experimental outcome. Most previous studies are however limited in one important aspect: individuals are treated as identical units. The aim of the proposed research proposed is to investigate features which produce differences within the units. The model systems of our study will be sticklebacks, homing pigeons and house sparrows. Individuals can differ from each other on a range of time scales, from information acquired within the last few minutes, through socially learnt information, to genetically inherited differences. Through a series of experiments on each of the study species, the development of mathematical models which incorporate between individual differences, and novel forms of data analysis, we will begin to understand the role played by individual differences within groups. We will look at the rules of motion for fish and birds; the role of personality in decision-making and how short term information differences improve decision-making accuracy. Achieving the project objectives will greatly enhance our understanding of the relationship between individual animals and the groups they live in, as well as impacting on our understanding of individual differences in other areas of biology.
Max ERC Funding
977 768 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym IMMUNEXPLORE
Project New approaches to analyze and exploit the human B and T cell response against viruses
Researcher (PI) Antonio Lanzavecchia
Host Institution (HI) FONDAZIONE PER L ISTITUTO DI RICERCA IN BIOMEDICINA
Country Switzerland
Call Details Advanced Grant (AdG), LS6, ERC-2009-AdG
Summary Immunological memory confers long term protection against pathogens and is the basis of successful vaccination.
Following antigenic stimulation long lived plasma cells and memory B cells are maintained for a lifetime, conferring immediate protection and enhanced responsiveness to the eliciting antigen. However, in the case of variable pathogens such as influenza virus, B cell memory is only partially effective, depending on the extent of similarity between the preceding and the new viruses. The B cell response is dominated by serotype-specific antibodies and heterosubtypic antibodies capable of neutralizing several serotypes appear to be extremely rare.
Understanding the basis of broadly neutralizing antibody responses is a critical aspect for the development of more effective vaccines. In this project we will explore the specificity and dynamics of human antibody responses to influenza virus by using newly developed technological platforms to culture human B cells and plasma cells and to analyze the repertoire of human naïve and memory T cells. High throughput functional screenings, structural analysis and testing in animal models will provide a thorough characterization of the human immune response. The B cell and T cell analysis aims at understanding fundamental aspects of the immune response such as: the selection and diversification of memory B cells; the individual variability of the antibody response, the mechanisms of T-B cooperation and the consequences of the original antigenic sin and of aging on the immune response. This analysis will be complemented by a translational approach whereby broadly neutralizing human monoclonal antibodies will be developed and used: i) for passive vaccination against highly variable viruses; ii) for vaccine design through the identification and production of recombinant antigens to be used as effective vaccines; and iii) for active vaccination in order to facilitate T cell priming and jump start the immune responses.
Summary
Immunological memory confers long term protection against pathogens and is the basis of successful vaccination.
Following antigenic stimulation long lived plasma cells and memory B cells are maintained for a lifetime, conferring immediate protection and enhanced responsiveness to the eliciting antigen. However, in the case of variable pathogens such as influenza virus, B cell memory is only partially effective, depending on the extent of similarity between the preceding and the new viruses. The B cell response is dominated by serotype-specific antibodies and heterosubtypic antibodies capable of neutralizing several serotypes appear to be extremely rare.
Understanding the basis of broadly neutralizing antibody responses is a critical aspect for the development of more effective vaccines. In this project we will explore the specificity and dynamics of human antibody responses to influenza virus by using newly developed technological platforms to culture human B cells and plasma cells and to analyze the repertoire of human naïve and memory T cells. High throughput functional screenings, structural analysis and testing in animal models will provide a thorough characterization of the human immune response. The B cell and T cell analysis aims at understanding fundamental aspects of the immune response such as: the selection and diversification of memory B cells; the individual variability of the antibody response, the mechanisms of T-B cooperation and the consequences of the original antigenic sin and of aging on the immune response. This analysis will be complemented by a translational approach whereby broadly neutralizing human monoclonal antibodies will be developed and used: i) for passive vaccination against highly variable viruses; ii) for vaccine design through the identification and production of recombinant antigens to be used as effective vaccines; and iii) for active vaccination in order to facilitate T cell priming and jump start the immune responses.
Max ERC Funding
1 979 200 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym IMMUNOSWITCH
Project Switch recombination: a model system for DNA editing and repair in human lymphocytes with relevance for primary immunodeficiency and cancer formation
Researcher (PI) Qiang Pan Hammarstroem
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Starting Grant (StG), LS6, ERC-2009-StG
Summary The aim of this project is to try to understand the complex molecular mechanisms involved in DNA editing, repair and recombination during immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). We have developed a series of PCR-based assays to study in vivo generated CSR junctions and the pattern of mutations introduced in the immunoglobulin variable region genes in human B cells, allowing us to characterize CSR and SHM in patients with immunodeficiency due to defect(s) in DNA repair/recombination. Novel in vitro CSR assays, based on GFP expression, allowing quantitative measurement of substrate recombination, are also being developed. In addition, we have initiated an evolutionary analysis of the function and structure of activation-induced deaminase, an essential molecule involved both in CSR and SHM, aiming to identify CSR specific-cofactor(s). Combining these approaches, we will be able to define the DNA repair pathways involved in CSR and SHM. The suggested project requires access to patients with various defects in the DNA repair pathways. Many of these diseases are exceedingly rare. However, through worldwide collaboration, we have obtained samples from a majority of the diagnosed patients. We are also refining the existing screening methods and developing novel methods, that will allow identification of additional patients both with recognized and new diseases caused by mutations in DNA repair pathways. Finally, we hope to be able to address the question whether illegitimate CSR events are associated with predisposition to lymphomagenesis in patients with immunodeficiency/DNA repair defect(s), by analyzing the CSR induced chromosomal breaks and translocations in these patients. A large-scale sequencing project is also planned to characterize the CSRnome in B-cell lymphoma samples.
Summary
The aim of this project is to try to understand the complex molecular mechanisms involved in DNA editing, repair and recombination during immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). We have developed a series of PCR-based assays to study in vivo generated CSR junctions and the pattern of mutations introduced in the immunoglobulin variable region genes in human B cells, allowing us to characterize CSR and SHM in patients with immunodeficiency due to defect(s) in DNA repair/recombination. Novel in vitro CSR assays, based on GFP expression, allowing quantitative measurement of substrate recombination, are also being developed. In addition, we have initiated an evolutionary analysis of the function and structure of activation-induced deaminase, an essential molecule involved both in CSR and SHM, aiming to identify CSR specific-cofactor(s). Combining these approaches, we will be able to define the DNA repair pathways involved in CSR and SHM. The suggested project requires access to patients with various defects in the DNA repair pathways. Many of these diseases are exceedingly rare. However, through worldwide collaboration, we have obtained samples from a majority of the diagnosed patients. We are also refining the existing screening methods and developing novel methods, that will allow identification of additional patients both with recognized and new diseases caused by mutations in DNA repair pathways. Finally, we hope to be able to address the question whether illegitimate CSR events are associated with predisposition to lymphomagenesis in patients with immunodeficiency/DNA repair defect(s), by analyzing the CSR induced chromosomal breaks and translocations in these patients. A large-scale sequencing project is also planned to characterize the CSRnome in B-cell lymphoma samples.
Max ERC Funding
1 888 166 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym INCEL
Project Revealing the molecular architecture of integrin mediated cell adhesion
Researcher (PI) Ohad Medalia
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Starting Grant (StG), LS1, ERC-2009-StG
Summary Cell adhesions play an important role in the organization, growth, maturation, and function of living cells. Interaction of cells with the extracellular matrix (ECM) plays an essential role in a variety of disease states , inflammation, and repair of damaged tissues. At the cellular level, many of the biological responses to external stimuli originate at adhesion loci, such as focal adhesions (FA), which link cells to the ECM . Cell adhesion is mediated by receptor proteins such as cadherins and integrins. The precise molecular composition, dynamics and signalling activity of these adhesion assemblies determine the specificity of adhesion-induced signals and their effects on the cell. However, characterization of the molecular architecture of FAs is highly challenging, and it thus remains unclear how these molecules function together, how they are recruited to the adhesion site, how they are turned over, and how they function in vivo. In this project, I aim to conduct an interdisciplinary study that will provide a quantum step forward in the understanding of the functional organization of FAs. We will analyze, for the first time, the three-dimensional structure of FAs in wild-type cells and in cells deficient in the specific proteins involved in the cell-adhesion machinery. We will study the effect of specific geometries on the functional architecture of focal adhesions in 3D. A combination of state-of-the-art technologies, such cryo-electron tomography of intact cells, gold cluster chemistry for in situ labeling, and modulation of the underlying matrix using micro- and nano-patterned adhesive surfaces, together with correlative light, atomic force and electron microscopy, will provide a hybrid approach for dissecting out the complex process of cell adhesion.In summary, this project addresses the properties of FAs across a wide range of complexities and dimensions, from macroscopic cellular phenomena to the physical nature of these molecular assemblies
Summary
Cell adhesions play an important role in the organization, growth, maturation, and function of living cells. Interaction of cells with the extracellular matrix (ECM) plays an essential role in a variety of disease states , inflammation, and repair of damaged tissues. At the cellular level, many of the biological responses to external stimuli originate at adhesion loci, such as focal adhesions (FA), which link cells to the ECM . Cell adhesion is mediated by receptor proteins such as cadherins and integrins. The precise molecular composition, dynamics and signalling activity of these adhesion assemblies determine the specificity of adhesion-induced signals and their effects on the cell. However, characterization of the molecular architecture of FAs is highly challenging, and it thus remains unclear how these molecules function together, how they are recruited to the adhesion site, how they are turned over, and how they function in vivo. In this project, I aim to conduct an interdisciplinary study that will provide a quantum step forward in the understanding of the functional organization of FAs. We will analyze, for the first time, the three-dimensional structure of FAs in wild-type cells and in cells deficient in the specific proteins involved in the cell-adhesion machinery. We will study the effect of specific geometries on the functional architecture of focal adhesions in 3D. A combination of state-of-the-art technologies, such cryo-electron tomography of intact cells, gold cluster chemistry for in situ labeling, and modulation of the underlying matrix using micro- and nano-patterned adhesive surfaces, together with correlative light, atomic force and electron microscopy, will provide a hybrid approach for dissecting out the complex process of cell adhesion.In summary, this project addresses the properties of FAs across a wide range of complexities and dimensions, from macroscopic cellular phenomena to the physical nature of these molecular assemblies
Max ERC Funding
1 294 000 €
Duration
Start date: 2009-11-01, End date: 2015-10-31
Project acronym INSYSBIO
Project Industrial Systems Biology of Yeast and A. oryzae
Researcher (PI) Jens Nielsen
Host Institution (HI) CHALMERS TEKNISKA HOEGSKOLA AB
Country Sweden
Call Details Advanced Grant (AdG), PE8, ERC-2009-AdG
Summary Metabolic engineering is the development of new cell factories or improving existing ones, and it is the enabling science that allows for sustainable production of fuels and chemicals through biotechnology. With the development in genomics and functional genomics, it has become interesting to evaluate how advanced high-throughput experimental techniques (transcriptome, proteome, metabolome and fluxome) can be applied for improving the process of metabolic engineering. These techniques have mainly found applications in life sciences and studies of human health, and it is necessary to develop novel bioinformatics techniques and modelling concepts before they can provide physiological information that can be used to guide metabolic engineering strategies. In particular it is challenging how these techniques can be used to advance the use of mathematical modelling for description of the operation of complex metabolic networks. The availability of robust mathematical models will allow a wider use of mathematical models to drive metabolic engineering, in analogy with other fields of engineering where mathematical modelling is central in the design phase. In this project the advancement of novel concepts, models and technologies for enhancing metabolic engineering will be done in connection with the development of novel cell factories for high-level production of different classes of products. The chemicals considered will involve both commodity type chemicals like 3-hydroxypropionic acid and malic acid, that can be used for sustainable production of polymers, an industrial enzyme and pharmaceutical proteins like human insulin.
Summary
Metabolic engineering is the development of new cell factories or improving existing ones, and it is the enabling science that allows for sustainable production of fuels and chemicals through biotechnology. With the development in genomics and functional genomics, it has become interesting to evaluate how advanced high-throughput experimental techniques (transcriptome, proteome, metabolome and fluxome) can be applied for improving the process of metabolic engineering. These techniques have mainly found applications in life sciences and studies of human health, and it is necessary to develop novel bioinformatics techniques and modelling concepts before they can provide physiological information that can be used to guide metabolic engineering strategies. In particular it is challenging how these techniques can be used to advance the use of mathematical modelling for description of the operation of complex metabolic networks. The availability of robust mathematical models will allow a wider use of mathematical models to drive metabolic engineering, in analogy with other fields of engineering where mathematical modelling is central in the design phase. In this project the advancement of novel concepts, models and technologies for enhancing metabolic engineering will be done in connection with the development of novel cell factories for high-level production of different classes of products. The chemicals considered will involve both commodity type chemicals like 3-hydroxypropionic acid and malic acid, that can be used for sustainable production of polymers, an industrial enzyme and pharmaceutical proteins like human insulin.
Max ERC Funding
2 499 590 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym INTGEN
Project Intergenerational correlations of schooling, income and health: an investigation of the underlying mechanisms
Researcher (PI) Carl Mikael Lindahl
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), SH1, ERC-2009-StG
Summary The objective of this project is to use rich Swedish registry data to learn about mechanisms behind intergenerational correlations. Typically, considerably effort has been spent on estimating correlations between outcome variables, such as education and income, for parents and children. However, the estimated correlations are driven by the causal effect of the parental variable of interest as well as unobservable factors such as other family background related variables and a part that is due to genetic transmission between parent and child. Disentangling these parts is very difficult and only recently has researchers made serious attempts to disentangling these different parts. However, findings vary widely across methods and this literature is still in its infancy. Among questions we ask are: How much of the association between outcome variables for the child and a parent is due to a causal effect from the parental variable, and how much is transmitted through unobservable family factors and genetic transmission? What are the intergenerational transmission and channels for life expectancy and health? What is the importance of genes-environmental interaction? Has the importance of genes, environment and its interactions for the intergenerational associations changed during the growth of the Scandinavian welfare state? How many generations does it take for ancestors placement in the income distribution to not longer matter for life success? These questions are directly relevant for policy, and relate to classical social science issues such as inequality of opportunity and level-of-living in general. The innovativeness of this project is based on using the uniqueness of Swedish registry data (ideal to answer these questions), with which one can match biological and adoptive parents, children and siblings, and hence can identify whether children are reared by their biological or adoptive parents, for the population of Swedes.
Summary
The objective of this project is to use rich Swedish registry data to learn about mechanisms behind intergenerational correlations. Typically, considerably effort has been spent on estimating correlations between outcome variables, such as education and income, for parents and children. However, the estimated correlations are driven by the causal effect of the parental variable of interest as well as unobservable factors such as other family background related variables and a part that is due to genetic transmission between parent and child. Disentangling these parts is very difficult and only recently has researchers made serious attempts to disentangling these different parts. However, findings vary widely across methods and this literature is still in its infancy. Among questions we ask are: How much of the association between outcome variables for the child and a parent is due to a causal effect from the parental variable, and how much is transmitted through unobservable family factors and genetic transmission? What are the intergenerational transmission and channels for life expectancy and health? What is the importance of genes-environmental interaction? Has the importance of genes, environment and its interactions for the intergenerational associations changed during the growth of the Scandinavian welfare state? How many generations does it take for ancestors placement in the income distribution to not longer matter for life success? These questions are directly relevant for policy, and relate to classical social science issues such as inequality of opportunity and level-of-living in general. The innovativeness of this project is based on using the uniqueness of Swedish registry data (ideal to answer these questions), with which one can match biological and adoptive parents, children and siblings, and hence can identify whether children are reared by their biological or adoptive parents, for the population of Swedes.
Max ERC Funding
631 600 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym LABCHIP_MULTIPLEX
Project Simultaneous Detection of Multiple DNA and Protein Targets on Paramagnetic Beads Packed in Microfluidic Channels using Quantum Dots as Tracers
Researcher (PI) Martin Pumera
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), PE4, ERC-2009-StG
Summary The detection of DNA hybridization and protein recoginittion event (immunoassay) is very important for the diagnosis and treatment of genetic diseases, for the detection infectious agents and for reliable forensic analysis. Recent activity has focused on the development of hybridization assays that permit simultaneous determination of multiple DNA or protein targets, using optical or electrochemical coding technology, based on unique encoding properties of semiconductor crystal nanoparticle tags (quantum dots). Described multi-target bio assays were performed in batch mode, involving significant amount of steps, connected with the possibility of human error, time and reagents consuming. Lab-on-a-chip technology offers tremendous potential for obtaining desired analytical information in a simpler, faster and cheaper way compared to traditional batch/laboratory-based technology. Particularly attractive for multiple DNA and protein recognition applications (i.e. point-of-care) is the high-throughput, automation, versatility, portability, reagent/sample economy and high-performance of such micromachined devices. Overall objective of the proposed research is to create and characterize a portable microanalyzer, based on a novel advanced Lab-on-a-Chip technology with magnetic separation and end-column quantum dots tracers voltammetric detection of multiple DNA and protein targets for point-of-care , automated, high-throughput, sensitive, selective and simultaneous assays. The new micro-total analytical system will rely on coupling of microfluidic transport of samples, effective flow-through magnetic separation complementary/non-complementary DNA and protein targets and a novel chip-based voltammetric stripping detection of quantum dot tags. To successfully complete such advanced micro-total analytical system, several fundamental and practical issues will be addressed.
Summary
The detection of DNA hybridization and protein recoginittion event (immunoassay) is very important for the diagnosis and treatment of genetic diseases, for the detection infectious agents and for reliable forensic analysis. Recent activity has focused on the development of hybridization assays that permit simultaneous determination of multiple DNA or protein targets, using optical or electrochemical coding technology, based on unique encoding properties of semiconductor crystal nanoparticle tags (quantum dots). Described multi-target bio assays were performed in batch mode, involving significant amount of steps, connected with the possibility of human error, time and reagents consuming. Lab-on-a-chip technology offers tremendous potential for obtaining desired analytical information in a simpler, faster and cheaper way compared to traditional batch/laboratory-based technology. Particularly attractive for multiple DNA and protein recognition applications (i.e. point-of-care) is the high-throughput, automation, versatility, portability, reagent/sample economy and high-performance of such micromachined devices. Overall objective of the proposed research is to create and characterize a portable microanalyzer, based on a novel advanced Lab-on-a-Chip technology with magnetic separation and end-column quantum dots tracers voltammetric detection of multiple DNA and protein targets for point-of-care , automated, high-throughput, sensitive, selective and simultaneous assays. The new micro-total analytical system will rely on coupling of microfluidic transport of samples, effective flow-through magnetic separation complementary/non-complementary DNA and protein targets and a novel chip-based voltammetric stripping detection of quantum dot tags. To successfully complete such advanced micro-total analytical system, several fundamental and practical issues will be addressed.
Max ERC Funding
1 400 000 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym LARGEMS
Project The Dynamic Composition of Protein Complexes: A New Perspective in Structural Biology
Researcher (PI) Michal Sharon
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Starting Grant (StG), PE4, ERC-2009-StG
Summary 80% of the proteome exists in complexes or large macromolecular assemblies. It is accepted that revealing the structure of these protein complexes is a key towards mechanistic understanding of cellular processes. Yet, this might not be sufficient; a higher level of complexity probably exists and protein complexes may not be static and uniform in form and function as thought. A protein complex may actually represent an ensemble of compositionally distinct entities with functional versatility. My main aim is to provide evidence for this conceptual change and to reveal the dynamic architecture of a protein assembly. As a model system, I will investigate the COP9 signalosome (CSN), an evolutionary conserved multisubunit complex, which is involved in a variety of essential functions ranging from cell-cycle progression, DNA-repair and apoptosis. My strategy is based on a comprehensive approach, made up of four main steps; i) Revealing the structural organization of the native complex. ii) Establishing whether the complex has co-existing independent modules that function separately of, or coordinately with the holocomplex. iii) Monitoring in real-time the biogenesis and activation pathway of the complex and developing an approach for shifting its oligomerization equilibrium. iv) Determining the correlation between modularity of the complex and cell cycle progression and comparing its composition in healthy versus cancerous cells. I will integrate genetic, biochemical and structural biology approaches. In particular, I will apply a state of the art mass spectrometry technique, that will enable us to define the stoichiometry, subunit composition, dynamic interactions and structural organization of protein complexes isolated directly from the cellular environment.
Summary
80% of the proteome exists in complexes or large macromolecular assemblies. It is accepted that revealing the structure of these protein complexes is a key towards mechanistic understanding of cellular processes. Yet, this might not be sufficient; a higher level of complexity probably exists and protein complexes may not be static and uniform in form and function as thought. A protein complex may actually represent an ensemble of compositionally distinct entities with functional versatility. My main aim is to provide evidence for this conceptual change and to reveal the dynamic architecture of a protein assembly. As a model system, I will investigate the COP9 signalosome (CSN), an evolutionary conserved multisubunit complex, which is involved in a variety of essential functions ranging from cell-cycle progression, DNA-repair and apoptosis. My strategy is based on a comprehensive approach, made up of four main steps; i) Revealing the structural organization of the native complex. ii) Establishing whether the complex has co-existing independent modules that function separately of, or coordinately with the holocomplex. iii) Monitoring in real-time the biogenesis and activation pathway of the complex and developing an approach for shifting its oligomerization equilibrium. iv) Determining the correlation between modularity of the complex and cell cycle progression and comparing its composition in healthy versus cancerous cells. I will integrate genetic, biochemical and structural biology approaches. In particular, I will apply a state of the art mass spectrometry technique, that will enable us to define the stoichiometry, subunit composition, dynamic interactions and structural organization of protein complexes isolated directly from the cellular environment.
Max ERC Funding
1 500 000 €
Duration
Start date: 2009-09-01, End date: 2014-08-31
Project acronym LAST
Project Large Scale Privacy-Preserving Technology in the Digital World - Infrastructure and Applications
Researcher (PI) Yehuda Lindell
Host Institution (HI) BAR ILAN UNIVERSITY
Country Israel
Call Details Starting Grant (StG), PE6, ERC-2009-StG
Summary Data mining provides large benefits to the commercial, government and homeland security sectors, but the aggregation and storage of huge amounts of data about citizens inevitably leads to erosion of privacy. To achieve the benefits that data mining has to offer, while at the same time enhancing privacy, we need technological solutions that simultaneously enable data mining while preserving privacy. The current state of the art has focused on providing privacy-preserving solutions for very specific problems, and has thus taken a local perspective. Although this is an important first step in the development of privacy-preserving solutions, it is time for a global perspective on the problem that aims for providing full integrated solutions. Our goal in this research is to study privacy and develop comprehensive solutions for enhancing it in the digital era. Our proposed research project includes foundational research on privacy, an infrastructure level for achieving anonymity over the Internet, key cryptographic tools for constructing privacy-preserving protocols, and development of large-scale applications that are built on top of all of the above. The novelty of our research is in our focus on fundamental issues towards comprehensive solutions that are aimed for large-scale data sources. The project s outcome will allow migration from local solutions for specific problems that are suited for small to medium scale data sources to comprehensive privacy-preserving database and data mining solutions for large scale data warehouses. Achieving this great challenge carries immense scientific, technological and societal rewards.
Summary
Data mining provides large benefits to the commercial, government and homeland security sectors, but the aggregation and storage of huge amounts of data about citizens inevitably leads to erosion of privacy. To achieve the benefits that data mining has to offer, while at the same time enhancing privacy, we need technological solutions that simultaneously enable data mining while preserving privacy. The current state of the art has focused on providing privacy-preserving solutions for very specific problems, and has thus taken a local perspective. Although this is an important first step in the development of privacy-preserving solutions, it is time for a global perspective on the problem that aims for providing full integrated solutions. Our goal in this research is to study privacy and develop comprehensive solutions for enhancing it in the digital era. Our proposed research project includes foundational research on privacy, an infrastructure level for achieving anonymity over the Internet, key cryptographic tools for constructing privacy-preserving protocols, and development of large-scale applications that are built on top of all of the above. The novelty of our research is in our focus on fundamental issues towards comprehensive solutions that are aimed for large-scale data sources. The project s outcome will allow migration from local solutions for specific problems that are suited for small to medium scale data sources to comprehensive privacy-preserving database and data mining solutions for large scale data warehouses. Achieving this great challenge carries immense scientific, technological and societal rewards.
Max ERC Funding
1 921 316 €
Duration
Start date: 2009-10-01, End date: 2014-09-30
Project acronym MAQD
Project Mathematical Aspects of Quantum Dynamics
Researcher (PI) Benjamin Schlein
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Starting Grant (StG), PE1, ERC-2009-StG
Summary The main goal of this proposal is to reach
a better mathematical understanding of
the dynamics of quantum mechanical
systems. In particular I plan to work
on the following three projects along
this direction. A. Effective Evolution
Equations for Macroscopic Systems.
The derivation of effective evolution
equations from first principle microscopic
theories is a fundamental task of statistical
mechanics. I have been involved in
several projects related to the derivation
of the Hartree and the Gross-Piteavskii
equation from many body quantum
dynamics. I plan to continue to work on
these problems and to use these results
to obtain new information on the many
body dynamics. B. Spectral Properties
of Random Matrices. The correlations
among eigenvalues of large random
matrices are expected to be independent
of the distribution of the entries. This
conjecture, known as universality, is
of great importance for random matrix
theory. In collaboration with L. Erdos and
H.-T. Yau, we established the validity of
Wigner's semicircle law on
microscopic scales, and we proved the
emergence of eigenvalue repulsion. In
the future, we plan to continue to study
Wigner matrices to prove, on the longer
term, universality. C. Locality Estimates in
Quantum Dynamics. Anharmonic lattice
systems are very important models in
non-equilibrium statistical mechanics.
With B. Nachtergaele, H. Raz, and R.
Sims, we proved Lieb-Robinson type
inequalities (giving an upper bound on
the speed of propagation of signals), for
a certain class of anharmonicity. Next, we
plan to extend these results to a larger
class of anharmonic potentials, and to
apply these bounds to establish other
fundamental properties of the dynamics
of anharmonic systems, such as the
existence of its thermodynamical limit.
Summary
The main goal of this proposal is to reach
a better mathematical understanding of
the dynamics of quantum mechanical
systems. In particular I plan to work
on the following three projects along
this direction. A. Effective Evolution
Equations for Macroscopic Systems.
The derivation of effective evolution
equations from first principle microscopic
theories is a fundamental task of statistical
mechanics. I have been involved in
several projects related to the derivation
of the Hartree and the Gross-Piteavskii
equation from many body quantum
dynamics. I plan to continue to work on
these problems and to use these results
to obtain new information on the many
body dynamics. B. Spectral Properties
of Random Matrices. The correlations
among eigenvalues of large random
matrices are expected to be independent
of the distribution of the entries. This
conjecture, known as universality, is
of great importance for random matrix
theory. In collaboration with L. Erdos and
H.-T. Yau, we established the validity of
Wigner's semicircle law on
microscopic scales, and we proved the
emergence of eigenvalue repulsion. In
the future, we plan to continue to study
Wigner matrices to prove, on the longer
term, universality. C. Locality Estimates in
Quantum Dynamics. Anharmonic lattice
systems are very important models in
non-equilibrium statistical mechanics.
With B. Nachtergaele, H. Raz, and R.
Sims, we proved Lieb-Robinson type
inequalities (giving an upper bound on
the speed of propagation of signals), for
a certain class of anharmonicity. Next, we
plan to extend these results to a larger
class of anharmonic potentials, and to
apply these bounds to establish other
fundamental properties of the dynamics
of anharmonic systems, such as the
existence of its thermodynamical limit.
Max ERC Funding
750 000 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym MATHFOR
Project Formalization of Constructive Mathematics
Researcher (PI) Thierry Coquand
Host Institution (HI) GOETEBORGS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), PE6, ERC-2009-AdG
Summary The general theme is to explore the connections between reasoning and computations in mathematics. There are two main research directions. The first research direction is a refomulation of Hilbert's program, using ideas from formal, or pointfree topology. We have shown, with multiple examples, that this allows a partial realization of this program in commutative algebra, and a new way to formulate constructive mathematics. The second research direction explores the computational content using type theory and the Curry-Howard correspondence between proofs and programs. Type theory allows us to represent constructive mathematics in a formal way, and provides key insight for the design of proof systems helping in the analysis of the logical structure of mathematical proofs. The interest of this program is well illustrated by the recent work of G. Gonthier on the formalization of the 4 color theorem.
Summary
The general theme is to explore the connections between reasoning and computations in mathematics. There are two main research directions. The first research direction is a refomulation of Hilbert's program, using ideas from formal, or pointfree topology. We have shown, with multiple examples, that this allows a partial realization of this program in commutative algebra, and a new way to formulate constructive mathematics. The second research direction explores the computational content using type theory and the Curry-Howard correspondence between proofs and programs. Type theory allows us to represent constructive mathematics in a formal way, and provides key insight for the design of proof systems helping in the analysis of the logical structure of mathematical proofs. The interest of this program is well illustrated by the recent work of G. Gonthier on the formalization of the 4 color theorem.
Max ERC Funding
1 912 288 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym MEDEA
Project Mechanisms of Epigenetic regulation in Development, Evolution and Adaptation
Researcher (PI) Ulrich Grossniklaus
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Advanced Grant (AdG), LS2, ERC-2009-AdG
Summary Over the last decade epigenetic gene regulation has become a major focus of scientific research as it was shown to play an important role in normal plant and animal development, but also in the ontogeny of human disease. A role of epigenetic processes in evolution, however, has found little general support to date. The goal of this project is to understand the complex interplay of epigenetic mechanisms in plant development and evolution. Many of the approaches we use rely on the recent advances in sequencing technologies, which allow the analysis of molecular characters at an unprecedented level and speed. To achieve our goal, we will focus on two epigenetic paradigms. In Program A, we will focus on dissecting the mechanisms of genomic imprinting at the MEDEA (MEA) locus in Arabidopsis, which we will investigate using genetic, molecular, and innovative biochemical approaches to gain a comprehensive picture of the complex interplay of various epigenetic pathways. In program B, we will analyze the role of epigenetic change in adaptation and evolution using (i) an experimental selection approach in Arabidopsis, where genome-wide analyses of epigenetic modifications have become possible, and (ii) a stable, heritable, epigenetic change occurring in Mimulus populations. In this system, an epigenetic switch of the pollinator syndrome leads to reproductive isolation and, therefore, has an effect on population structure and thus the evolutionary trajectory. These experimental systems each offer unique opportunities to shed light onto the underlying mechanisms controlling epigenetic states. In combination with the new methodologies used, these analyses promise to provide step change in our understanding of epigenetic processes at the level of genes, organisms, and populations.
Summary
Over the last decade epigenetic gene regulation has become a major focus of scientific research as it was shown to play an important role in normal plant and animal development, but also in the ontogeny of human disease. A role of epigenetic processes in evolution, however, has found little general support to date. The goal of this project is to understand the complex interplay of epigenetic mechanisms in plant development and evolution. Many of the approaches we use rely on the recent advances in sequencing technologies, which allow the analysis of molecular characters at an unprecedented level and speed. To achieve our goal, we will focus on two epigenetic paradigms. In Program A, we will focus on dissecting the mechanisms of genomic imprinting at the MEDEA (MEA) locus in Arabidopsis, which we will investigate using genetic, molecular, and innovative biochemical approaches to gain a comprehensive picture of the complex interplay of various epigenetic pathways. In program B, we will analyze the role of epigenetic change in adaptation and evolution using (i) an experimental selection approach in Arabidopsis, where genome-wide analyses of epigenetic modifications have become possible, and (ii) a stable, heritable, epigenetic change occurring in Mimulus populations. In this system, an epigenetic switch of the pollinator syndrome leads to reproductive isolation and, therefore, has an effect on population structure and thus the evolutionary trajectory. These experimental systems each offer unique opportunities to shed light onto the underlying mechanisms controlling epigenetic states. In combination with the new methodologies used, these analyses promise to provide step change in our understanding of epigenetic processes at the level of genes, organisms, and populations.
Max ERC Funding
2 496 641 €
Duration
Start date: 2010-04-01, End date: 2015-12-31
Project acronym MESOLIGHT
Project Mesoscopic Junctions for Light Energy Harvesting and Conversion
Researcher (PI) Michael Graetzel
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), PE5, ERC-2009-AdG
Summary Research will focus on the generation of electric power by mesoscopic solar cells, a domain where the PI has an outstanding track record and leadership on the global scale. The target is to increase the photovoltaic conversion efficiency from currently 11 to over 15 percent rendering these new solar cells very attractive for applications in large areas of photovoltaic electricity production. The approach to reach this challenging target is highly creative and has a strongly interdisciplinary character. Successful implementation of the project goals is assured by the vast experience and know how of the PI and his team in the key areas of the project. The project is divided in four work packages. The first three introduce creative new concepts to enhance substantially the performance of single-junction dye sensitized nanocrystalline devices, while the fourth addresses multi-junction cells and photon up-conversion systems. The tasks to be accomplished comprise 1) The theoretically assisted conception and synthesis of new molecular sensitizers to extend the spectral response of dye sensitized photovoltaic cells into the near IR up to 900 nm, increasing substantially the short circuit photocurrent of the solar cell. 2) The implementation of highly innovative mesoscopic oxides structures to support the molecular dye or quantum dot and collect the photo-generated charge carriers. 3) The introduction of smart amphiphilic molecular insulators and ultra-thin ceramic barriers at the mesoscopic junction in order to retard the interfacial electron-hole recombination and 4) The exploration of radically new cell embodiments based on multi-junction tandem cells and photon up-conversion schemes, whose solar to electric power conversion efficiency can be raised beyond the Shockley-Queiser limit of 32 percent.
Summary
Research will focus on the generation of electric power by mesoscopic solar cells, a domain where the PI has an outstanding track record and leadership on the global scale. The target is to increase the photovoltaic conversion efficiency from currently 11 to over 15 percent rendering these new solar cells very attractive for applications in large areas of photovoltaic electricity production. The approach to reach this challenging target is highly creative and has a strongly interdisciplinary character. Successful implementation of the project goals is assured by the vast experience and know how of the PI and his team in the key areas of the project. The project is divided in four work packages. The first three introduce creative new concepts to enhance substantially the performance of single-junction dye sensitized nanocrystalline devices, while the fourth addresses multi-junction cells and photon up-conversion systems. The tasks to be accomplished comprise 1) The theoretically assisted conception and synthesis of new molecular sensitizers to extend the spectral response of dye sensitized photovoltaic cells into the near IR up to 900 nm, increasing substantially the short circuit photocurrent of the solar cell. 2) The implementation of highly innovative mesoscopic oxides structures to support the molecular dye or quantum dot and collect the photo-generated charge carriers. 3) The introduction of smart amphiphilic molecular insulators and ultra-thin ceramic barriers at the mesoscopic junction in order to retard the interfacial electron-hole recombination and 4) The exploration of radically new cell embodiments based on multi-junction tandem cells and photon up-conversion schemes, whose solar to electric power conversion efficiency can be raised beyond the Shockley-Queiser limit of 32 percent.
Max ERC Funding
2 046 000 €
Duration
Start date: 2010-03-01, End date: 2015-02-28
Project acronym METABOLOMIRS
Project Elucidation of MicroRNAs as Regulators of Metabolism and Targets for Therapeutic Intervention
Researcher (PI) Markus Stoffel
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary Small RNA-mediated regulation of gene expression is a recent addition to fundamental gene regulatory mechanisms that directly or indirectly affect possibly every gene of a eukaryotic genome. The predominant sources of small RNA in somatic tissues are microRNA genes that encode short dsRNA hairpins of evolutionary conserved sequence. Disorders of metabolism, such as obesity and type 2 diabetes are poorly understood at a molecular level. In this application we propose to explore if miRNA regulatory networks play a role in these diseases. We will employ state of the art methods for identification of small RNAs and their regulated targets and use biochemical, cell and animal model systems to study the detailed molecular mechanisms of metabolic gene regulation by miRNAs. In addition, we will investigate the underlying principles of how RNAs are taken up by cells and develop methods that will improve delivery of miRNA mimetics or inhibitors through cell-specific uptake. The specific aims of this study are: Aim 1: To define the small regulatory miRNA content of liver, muscle and adipose tissue that are associated with abnormal glucose and lipid homeostasis and to dissect the underlying molecular pathways that govern their expression. Aim 2: To characterize the functions of miRNAs in insulin resistance, glucose uptake and production, fatty acid oxidation and lipogenesis. Aim 3: To identify factors and dissect the pathways that regulate RNA uptake by cells and to develop novel pharmacological treatment strategies to manipulate miRNA-expression. Together, this proposal will shed light on the function that miRNA regulatory networks play in metabolism and in the pathophysiology of obesity/type 2 diabetes. In addition, these studies will contribute to the development of new RNA delivery technologies that are urgently needed as experimental tools as well as for novel therapeutic strategies.
Summary
Small RNA-mediated regulation of gene expression is a recent addition to fundamental gene regulatory mechanisms that directly or indirectly affect possibly every gene of a eukaryotic genome. The predominant sources of small RNA in somatic tissues are microRNA genes that encode short dsRNA hairpins of evolutionary conserved sequence. Disorders of metabolism, such as obesity and type 2 diabetes are poorly understood at a molecular level. In this application we propose to explore if miRNA regulatory networks play a role in these diseases. We will employ state of the art methods for identification of small RNAs and their regulated targets and use biochemical, cell and animal model systems to study the detailed molecular mechanisms of metabolic gene regulation by miRNAs. In addition, we will investigate the underlying principles of how RNAs are taken up by cells and develop methods that will improve delivery of miRNA mimetics or inhibitors through cell-specific uptake. The specific aims of this study are: Aim 1: To define the small regulatory miRNA content of liver, muscle and adipose tissue that are associated with abnormal glucose and lipid homeostasis and to dissect the underlying molecular pathways that govern their expression. Aim 2: To characterize the functions of miRNAs in insulin resistance, glucose uptake and production, fatty acid oxidation and lipogenesis. Aim 3: To identify factors and dissect the pathways that regulate RNA uptake by cells and to develop novel pharmacological treatment strategies to manipulate miRNA-expression. Together, this proposal will shed light on the function that miRNA regulatory networks play in metabolism and in the pathophysiology of obesity/type 2 diabetes. In addition, these studies will contribute to the development of new RNA delivery technologies that are urgently needed as experimental tools as well as for novel therapeutic strategies.
Max ERC Funding
2 021 235 €
Duration
Start date: 2010-07-01, End date: 2015-06-30
Project acronym MFECE
Project Magnetostrophic Flow in Experiments and the Core of the Earth
Researcher (PI) Andrew Jackson
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Advanced Grant (AdG), PE10, ERC-2009-AdG
Summary We describe here an innovative strategy for understanding the so-called magnetostrophic regime of fluid flow in the Earth s core, and thus the mechanisms by which the Earth s magnetic field is sustained over time. The magnetostrophic regime is the state in which Lorentz (magnetic) forces are balanced by Coriolis (rotational) forces and pressure gradients and is thought to be the zeroth order force balance in the core. We propose a series of ground-breaking experiments using liquid sodium contained in a rapidly rotating sphere containing a differentially rotating solid inner sphere. For the first time electric current is injected into the fluid in different configurations in order that the Lorentz force is everywhere significant. Various other magnetic fields can be applied from the exterior and the interior. The influence of turbulence, viscous and magnetic boundary layers will be examined. The presence of instabilities and wave motion will be studied, and the existence of steady solutions will be naturally determined. Diagnostic measurements of magnetic fields and electrical potentials, and Doppler velocimetry will characterise the experiment. These unique experiments are backed by numerical calculations. Complementary studies will analyse the observed magnetic field over the last 400 years in the same magnetostrophic framework. An inverse method will be developed to find the initial state of the field that evolves in a manner compatible with observations. This will elucidate the interior structure of the magnetic field for the first time, determining the amplitude and morphology of the field. The importance of magnetic diffusion (Joule heating) will arise naturally, and fluid motion in the entire core will be found, allowing comparison with geodetic observations.
Summary
We describe here an innovative strategy for understanding the so-called magnetostrophic regime of fluid flow in the Earth s core, and thus the mechanisms by which the Earth s magnetic field is sustained over time. The magnetostrophic regime is the state in which Lorentz (magnetic) forces are balanced by Coriolis (rotational) forces and pressure gradients and is thought to be the zeroth order force balance in the core. We propose a series of ground-breaking experiments using liquid sodium contained in a rapidly rotating sphere containing a differentially rotating solid inner sphere. For the first time electric current is injected into the fluid in different configurations in order that the Lorentz force is everywhere significant. Various other magnetic fields can be applied from the exterior and the interior. The influence of turbulence, viscous and magnetic boundary layers will be examined. The presence of instabilities and wave motion will be studied, and the existence of steady solutions will be naturally determined. Diagnostic measurements of magnetic fields and electrical potentials, and Doppler velocimetry will characterise the experiment. These unique experiments are backed by numerical calculations. Complementary studies will analyse the observed magnetic field over the last 400 years in the same magnetostrophic framework. An inverse method will be developed to find the initial state of the field that evolves in a manner compatible with observations. This will elucidate the interior structure of the magnetic field for the first time, determining the amplitude and morphology of the field. The importance of magnetic diffusion (Joule heating) will arise naturally, and fluid motion in the entire core will be found, allowing comparison with geodetic observations.
Max ERC Funding
3 116 900 €
Duration
Start date: 2010-05-01, End date: 2016-04-30
Project acronym MICRONANO
Project Modeling Brain Circuitry using Scales Ranging from Micrometer to Nanometer
Researcher (PI) Pascal Fua
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), PE6, ERC-2009-AdG
Summary If we are ever to unravel the mysteries of brain function at its most fundamental level, we will need a precise understanding of how its component neurons connect to each other. Furthermore, given the many recent advances in genetic engineering, viral targeting, and immunohistochemical labeling of specific cellular structures, there is a growing need for automated quantitative assessment of neuron morphology and connectivity. Electron microscopes can now provide the nanometer resolution that is needed to image synapses, and therefore connections, while Light Microscopes see at the micrometer resolution required to model the 3D structure of the dendritic network. Since both the arborescence and the connections are integral parts of the brain's wiring diagram, combining these two modalities is critically important. In fact, these microscopes now routinely produce high-resolution imagery in such large quantities that the bottleneck becomes automated processing and interpretation, which is needed for such data to be exploited to its full potential. We will therefore use our Computer Vision expertise to provide not only the necessary tools to process images acquired using a specific modality but also those required to create an integrated representation using all available modalities. This is a radical departure from earlier approaches to applying Computer Vision techniques in this field, which have tended to focus on narrow problems. State-of-the-art methods have not reached the level of reliability and integration that would allow automated processing and interpretation of the massive amounts of data that are required for a true leap of our understanding of how the brain works. In other words, we cannot yet exploit the full potential of our imaging technology and that is what we intend to change.
Summary
If we are ever to unravel the mysteries of brain function at its most fundamental level, we will need a precise understanding of how its component neurons connect to each other. Furthermore, given the many recent advances in genetic engineering, viral targeting, and immunohistochemical labeling of specific cellular structures, there is a growing need for automated quantitative assessment of neuron morphology and connectivity. Electron microscopes can now provide the nanometer resolution that is needed to image synapses, and therefore connections, while Light Microscopes see at the micrometer resolution required to model the 3D structure of the dendritic network. Since both the arborescence and the connections are integral parts of the brain's wiring diagram, combining these two modalities is critically important. In fact, these microscopes now routinely produce high-resolution imagery in such large quantities that the bottleneck becomes automated processing and interpretation, which is needed for such data to be exploited to its full potential. We will therefore use our Computer Vision expertise to provide not only the necessary tools to process images acquired using a specific modality but also those required to create an integrated representation using all available modalities. This is a radical departure from earlier approaches to applying Computer Vision techniques in this field, which have tended to focus on narrow problems. State-of-the-art methods have not reached the level of reliability and integration that would allow automated processing and interpretation of the massive amounts of data that are required for a true leap of our understanding of how the brain works. In other words, we cannot yet exploit the full potential of our imaging technology and that is what we intend to change.
Max ERC Funding
2 495 982 €
Duration
Start date: 2010-04-01, End date: 2016-03-31
Project acronym MINE
Project Molecular Interfacial structure and dynamics of Nanoscopic droplets in Emulsions (MINE)
Researcher (PI) Sylvie Roke
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), PE4, ERC-2009-StG
Summary Emulsions consist of one liquid dispersed as nanoscopic droplets in another liquid, such as milk, and butter. The understanding of the structure and stability of emulsions is commonly obtained from empirical studies in which a macroscopic parameter (like temperature or concentration of constituents) is varied. Since the work of Irving Langmuir and others (published in 1917) it is well established that the stability and properties of these nanoscopic droplets are strongly influenced by the state of the droplet interface. However, despite the abundance and importance of emulsions in our daily lives, the molecular mechanisms that dictate the stability and properties of emulsions are still unknown. This lack of insight is caused by the system itself: the condensed surrounding medium forms an impenetrable barrier to most molecular probes. Nonlinear light scattering spectroscopy, a novel method I have developed (both theoretically and experimentally), offers a way of obtaining molecular information (chemical composition, molecular orientation, ordering and chirality) of the interfaces of nanoscopic particles in solution. With this method it should be possible to observe, in-situ, non-invasively and label-free, the molecules at the interface of the nanoscopic droplets in solution. I therefore propose to form a small group that investigates interfaces of nanoscopic droplets in emulsions on the molecular level and timescale. Using femtosecond nonlinear light scattering methods we can finally observe the molecules that dictate the structure and stability of emulsions in action.
Summary
Emulsions consist of one liquid dispersed as nanoscopic droplets in another liquid, such as milk, and butter. The understanding of the structure and stability of emulsions is commonly obtained from empirical studies in which a macroscopic parameter (like temperature or concentration of constituents) is varied. Since the work of Irving Langmuir and others (published in 1917) it is well established that the stability and properties of these nanoscopic droplets are strongly influenced by the state of the droplet interface. However, despite the abundance and importance of emulsions in our daily lives, the molecular mechanisms that dictate the stability and properties of emulsions are still unknown. This lack of insight is caused by the system itself: the condensed surrounding medium forms an impenetrable barrier to most molecular probes. Nonlinear light scattering spectroscopy, a novel method I have developed (both theoretically and experimentally), offers a way of obtaining molecular information (chemical composition, molecular orientation, ordering and chirality) of the interfaces of nanoscopic particles in solution. With this method it should be possible to observe, in-situ, non-invasively and label-free, the molecules at the interface of the nanoscopic droplets in solution. I therefore propose to form a small group that investigates interfaces of nanoscopic droplets in emulsions on the molecular level and timescale. Using femtosecond nonlinear light scattering methods we can finally observe the molecules that dictate the structure and stability of emulsions in action.
Max ERC Funding
1 150 000 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym MINT
Project Multiphoton Ionization Nano-Therapy
Researcher (PI) Dvir Yelin
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Country Israel
Call Details Starting Grant (StG), PE7, ERC-2009-StG
Summary The application of nanotechnology for addressing key problems in clinical diagnosis and therapy holds great promise in medicine and in cancer in particular. Recent works have shown significant progress in nanoparticle-mediated drug delivery and therapy. In these applications, however, the small dimensions of the nanoparticles have been used primarily for efficient delivery and specificity, while the effects mediated by the nanoparticles occur away from the particle itself, affecting the entire cell\tumour volume. We propose to study and develop, for the first time, a novel scheme for cancer therapy that treats cancer cells at nanoscale resolutions. Briefly, when noble-metal nanoparticles are illuminated with femtosecond laser pulses tuned to their plasmonic resonance, order-of-magnitude enhancements of the optical fields several nanometres away from their surfaces lead to local damage only to nearby molecules or cellular organelles. This process, which practically involves no toxic agents, is at the basis for this proposal; we will utilize techniques for targeting nanoparticles to cells, initiate and control cancer cell destruction using nanoparticles and femtosecond laser pulses, and develop technology for conducting image-guided minimally invasive cancer therapy in remote locations of the body. Preliminary results supporting the proposed scheme include nonlinear optical imaging and ablation of living cells, in vivo endoscopic imaging of cancerous tumour nodules, and computer simulations of light-nanoparticle interactions. Using state-of-the-art concepts in nanotechnology, biology, chemistry, and medicine, the proposed novel multidisciplinary research will attempt at offering a feasible and safe addition to existing forms of cancer therapy.
Summary
The application of nanotechnology for addressing key problems in clinical diagnosis and therapy holds great promise in medicine and in cancer in particular. Recent works have shown significant progress in nanoparticle-mediated drug delivery and therapy. In these applications, however, the small dimensions of the nanoparticles have been used primarily for efficient delivery and specificity, while the effects mediated by the nanoparticles occur away from the particle itself, affecting the entire cell\tumour volume. We propose to study and develop, for the first time, a novel scheme for cancer therapy that treats cancer cells at nanoscale resolutions. Briefly, when noble-metal nanoparticles are illuminated with femtosecond laser pulses tuned to their plasmonic resonance, order-of-magnitude enhancements of the optical fields several nanometres away from their surfaces lead to local damage only to nearby molecules or cellular organelles. This process, which practically involves no toxic agents, is at the basis for this proposal; we will utilize techniques for targeting nanoparticles to cells, initiate and control cancer cell destruction using nanoparticles and femtosecond laser pulses, and develop technology for conducting image-guided minimally invasive cancer therapy in remote locations of the body. Preliminary results supporting the proposed scheme include nonlinear optical imaging and ablation of living cells, in vivo endoscopic imaging of cancerous tumour nodules, and computer simulations of light-nanoparticle interactions. Using state-of-the-art concepts in nanotechnology, biology, chemistry, and medicine, the proposed novel multidisciplinary research will attempt at offering a feasible and safe addition to existing forms of cancer therapy.
Max ERC Funding
1 782 600 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym MIRTURN
Project Mechanisms of microRNA biogenesis and turnover
Researcher (PI) Helge Grosshans
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Country Switzerland
Call Details Starting Grant (StG), LS2, ERC-2009-StG
Summary MicroRNAs (miRNAs) are a novel class of genes, accounting for >1% of genes in a typical animal genome. They constitute an important layer of gene regulation that affects diverse processes such as cell differentiation, apoptosis, and metabolism. Despite such critical roles, deciphering the mechanism of action of miRNAs has been difficult, leading to multiple, partially contradictory, models of miRNA activity. Moreover, adding an additional layer of complexity, it is now emerging that miRNA activity is regulated by various mechanisms that we are only beginning to identify. Our objective is to understand how miRNAs are regulated under physiological conditions, in the roundworm Caenorhabditis elegans. We will focus on pathways of miRNA turnover, an issue of fundamental importance that has received little attention because miRNAs are widely held to be highly stable molecules. However, miRNA over-accumulation causes aberrant development and disease, prompting us to test rigorously whether degradation can antagonize miRNA activity and either identify the machinery involved, or confirm the dominance of other regulatory modalities, whose components we will identify. C. elegans is the organism in which miRNAs and many components of the miRNA machinery were discovered. However, previous studies emphasized genetics and cell biology approaches, limiting the degree of mechanistic insight that could be obtained. In addition to exploiting the traditional strengths of C. elegans, we will therefore develop and apply biochemical and genomic techniques to obtain a comprehensive understanding of miRNA regulation, enabling us to demonstrate both molecular mechanisms and physiological relevance. Given the importance of miRNAs in development and disease, identifying the regulators of these tiny gene regulators will be both of scientific interest and biomedical relevance.
Summary
MicroRNAs (miRNAs) are a novel class of genes, accounting for >1% of genes in a typical animal genome. They constitute an important layer of gene regulation that affects diverse processes such as cell differentiation, apoptosis, and metabolism. Despite such critical roles, deciphering the mechanism of action of miRNAs has been difficult, leading to multiple, partially contradictory, models of miRNA activity. Moreover, adding an additional layer of complexity, it is now emerging that miRNA activity is regulated by various mechanisms that we are only beginning to identify. Our objective is to understand how miRNAs are regulated under physiological conditions, in the roundworm Caenorhabditis elegans. We will focus on pathways of miRNA turnover, an issue of fundamental importance that has received little attention because miRNAs are widely held to be highly stable molecules. However, miRNA over-accumulation causes aberrant development and disease, prompting us to test rigorously whether degradation can antagonize miRNA activity and either identify the machinery involved, or confirm the dominance of other regulatory modalities, whose components we will identify. C. elegans is the organism in which miRNAs and many components of the miRNA machinery were discovered. However, previous studies emphasized genetics and cell biology approaches, limiting the degree of mechanistic insight that could be obtained. In addition to exploiting the traditional strengths of C. elegans, we will therefore develop and apply biochemical and genomic techniques to obtain a comprehensive understanding of miRNA regulation, enabling us to demonstrate both molecular mechanisms and physiological relevance. Given the importance of miRNAs in development and disease, identifying the regulators of these tiny gene regulators will be both of scientific interest and biomedical relevance.
Max ERC Funding
1 782 200 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym MOTOR CIRCUITS
Project Neuronal circuits controlling motor behavior
Researcher (PI) Silvia Isabelle Arber
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Country Switzerland
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary How does the assembly of neuronal circuits contribute to the emergence of function controlling dedicated animal behaviors? Finding answers to this question requires a deep understanding of the connectivity map of neuronal circuits controlling a behavior as well as the mechanisms involved in the generation of these specific circuit maps. In the project outlined here, I propose the analysis of the neuronal circuits involved in the generation of motor output, a behavior representing the ultimate output of nearly all nervous system activity. Studying the mouse motor output system will allow the analysis of neuronal circuit connectivity at an exquisite degree of specificity. Owing to the anatomical arrangement of motor neuron pools innervating individual muscles, this system offers the possibility to combine genetic, anatomical and physiological analysis of synaptic specificity with a direct link to a behavioral output. Generation of coordinated motor behavior is functionally linked to the high degree of specificity in presynaptic connections controlling the activation of individual motor neuron pools, yet knowledge on the specificity map of premotor circuits is currently missing. The aim of this research project is to acquire information on the general principles guiding the acquisition, maintenance and developmental plasticity of neuronal connectivity between premotor neurons and functionally defined subpopulations of motor neurons. This project is now possible due to the unique combination of our detailed know-how of the motor system in mice including a variety of genetic animal models, and the application of novel viral circuit tracing technology revealing monosynaptically connected premotor neurons, which we have recently applied successfully to the motor system in mice in vivo. Together, our project will elucidate the anatomical connectome of the motor output system as well as the principles governing the specificity with which motor circuits assemble.
Summary
How does the assembly of neuronal circuits contribute to the emergence of function controlling dedicated animal behaviors? Finding answers to this question requires a deep understanding of the connectivity map of neuronal circuits controlling a behavior as well as the mechanisms involved in the generation of these specific circuit maps. In the project outlined here, I propose the analysis of the neuronal circuits involved in the generation of motor output, a behavior representing the ultimate output of nearly all nervous system activity. Studying the mouse motor output system will allow the analysis of neuronal circuit connectivity at an exquisite degree of specificity. Owing to the anatomical arrangement of motor neuron pools innervating individual muscles, this system offers the possibility to combine genetic, anatomical and physiological analysis of synaptic specificity with a direct link to a behavioral output. Generation of coordinated motor behavior is functionally linked to the high degree of specificity in presynaptic connections controlling the activation of individual motor neuron pools, yet knowledge on the specificity map of premotor circuits is currently missing. The aim of this research project is to acquire information on the general principles guiding the acquisition, maintenance and developmental plasticity of neuronal connectivity between premotor neurons and functionally defined subpopulations of motor neurons. This project is now possible due to the unique combination of our detailed know-how of the motor system in mice including a variety of genetic animal models, and the application of novel viral circuit tracing technology revealing monosynaptically connected premotor neurons, which we have recently applied successfully to the motor system in mice in vivo. Together, our project will elucidate the anatomical connectome of the motor output system as well as the principles governing the specificity with which motor circuits assemble.
Max ERC Funding
2 499 354 €
Duration
Start date: 2010-03-01, End date: 2016-02-29
Project acronym NANOSYS
Project Nanosystems: Architectures, Design and Applications
Researcher (PI) Giovanni De Micheli
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), PE6, ERC-2009-AdG
Summary Nanosystems are integrated systems exploiting nanoelectronic devices. In particular, this proposal considers silicon nanowire and carbon nanotube technologies as replacement/enhancement of current silicon technologies. This proposal addresses high-risk, high-reward research, unique in its kind. The broad objective of this proposal is to study system organization, architectures and design tools which, based on a deep understanding and abstraction of the manufacturing technologies, allow us to realize nanosystems that outperform current integrated systems in terms of capabilities and performance. Thus this proposal will address modelling of technological aspects, synthesis and optimization of information processing functions from high-level specifications into the nanofabric, and new design technologies for specific aspects of nanosystems including, but not limited to, sensing and interfacing with the environment. This proposal will address also cross-cutting design goals such as ultra-low power and high-dependability design, with the overall objective of realizing nanosystems that are autonomous (w.r. to energy consumption) and autonomic (i.e., self healing). The scientific novelty of this proposal stems from the use of a nanofabric, where computation, sensing and communication are supported by a homogeneous means as well as from the study of algorithmic tools for mapping high-level functions onto the nanofabric. The intrinsic benefit of this research is to provide a design flow that extends both the technological basis and the capabilities of integrated systems, thus strengthening the industrial European position in a key sector where disruptive innovation is key for survival. The extrinsic benefit of this research is to broaden the use of nanosystems to new domains, including mobile/distributed embedded systems, health/environment management, and other areas that are critical to our lives.
Summary
Nanosystems are integrated systems exploiting nanoelectronic devices. In particular, this proposal considers silicon nanowire and carbon nanotube technologies as replacement/enhancement of current silicon technologies. This proposal addresses high-risk, high-reward research, unique in its kind. The broad objective of this proposal is to study system organization, architectures and design tools which, based on a deep understanding and abstraction of the manufacturing technologies, allow us to realize nanosystems that outperform current integrated systems in terms of capabilities and performance. Thus this proposal will address modelling of technological aspects, synthesis and optimization of information processing functions from high-level specifications into the nanofabric, and new design technologies for specific aspects of nanosystems including, but not limited to, sensing and interfacing with the environment. This proposal will address also cross-cutting design goals such as ultra-low power and high-dependability design, with the overall objective of realizing nanosystems that are autonomous (w.r. to energy consumption) and autonomic (i.e., self healing). The scientific novelty of this proposal stems from the use of a nanofabric, where computation, sensing and communication are supported by a homogeneous means as well as from the study of algorithmic tools for mapping high-level functions onto the nanofabric. The intrinsic benefit of this research is to provide a design flow that extends both the technological basis and the capabilities of integrated systems, thus strengthening the industrial European position in a key sector where disruptive innovation is key for survival. The extrinsic benefit of this research is to broaden the use of nanosystems to new domains, including mobile/distributed embedded systems, health/environment management, and other areas that are critical to our lives.
Max ERC Funding
2 499 594 €
Duration
Start date: 2010-04-01, End date: 2015-12-31
Project acronym NEUROCHEMS
Project From neurons to behavior: analysis of the mechanisms underlying sensory coding and plasticity in chemical senses
Researcher (PI) Alan, Jacques, Henri, Cyrus Carleton
Host Institution (HI) UNIVERSITE DE GENEVE
Country Switzerland
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary How sensory processing is occurring into the brain and how to relate behavior to neuronal activities are key questions in modern neuroscience. Understanding the neural codes underlying brain function will be of great importance for future implementation of brain-machine interfaces. This research project proposes to study the cellular and network mechanisms controlling sensory perception. In particular, we would like to precise how sensory stimuli are coded by brain networks and how these representations may be influenced by experience or modulatory brain centers. In order to address these general questions, we propose to study olfaction as model sensory system. The olfactory system is central to the behavior of rodents (animal models that we study), is highly plastic and largely modulated by the neuromodulatory brain centers. We propose to use a combination of genetic, electrophysiological, imaging and behavioral methods to study how odor information is processed in the central nervous system as it moves from the periphery to higher areas of the brain. We showed in the past that sensory information can be contained in dynamic neural ensemble. We propose to show that ensemble dynamics may be the basis of odor coding in the olfactory bulb and to describe the mechanisms underlying cortical coding that would allow us to relate neuronal activity to behavior. In addition, we hope to show the existence of a novel form of plasticity in the olfactory bulb namely ensemble plasticity. We believe that the general questions addressed in the study of these sensory systems go beyond understanding olfactory sensory perception and could potentially be generalized to the function of many brain regions.
Summary
How sensory processing is occurring into the brain and how to relate behavior to neuronal activities are key questions in modern neuroscience. Understanding the neural codes underlying brain function will be of great importance for future implementation of brain-machine interfaces. This research project proposes to study the cellular and network mechanisms controlling sensory perception. In particular, we would like to precise how sensory stimuli are coded by brain networks and how these representations may be influenced by experience or modulatory brain centers. In order to address these general questions, we propose to study olfaction as model sensory system. The olfactory system is central to the behavior of rodents (animal models that we study), is highly plastic and largely modulated by the neuromodulatory brain centers. We propose to use a combination of genetic, electrophysiological, imaging and behavioral methods to study how odor information is processed in the central nervous system as it moves from the periphery to higher areas of the brain. We showed in the past that sensory information can be contained in dynamic neural ensemble. We propose to show that ensemble dynamics may be the basis of odor coding in the olfactory bulb and to describe the mechanisms underlying cortical coding that would allow us to relate neuronal activity to behavior. In addition, we hope to show the existence of a novel form of plasticity in the olfactory bulb namely ensemble plasticity. We believe that the general questions addressed in the study of these sensory systems go beyond understanding olfactory sensory perception and could potentially be generalized to the function of many brain regions.
Max ERC Funding
1 399 998 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym NEXTGENMOLECOL
Project Next Generation Molecular Ecology
Researcher (PI) Hans Ellegren
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), LS8, ERC-2009-AdG
Summary There is an immediate need to increase our understanding of the genetic basis for fitness differences in natural populations (Ellegren and Sheldon Nature 452:169-175, 2008). Fortunately, technological developments within genome research, notably the recent ability to retrieve massive amounts of DNA sequence data based on next generation sequencing , will make possible completely novel investigations of the link between genotypes and phenotypes in non-model organisms. With our background as major players in molecular ecology and evolutionary genomics of non-models for the last 15-20 years, we are excellently placed to take on a leading role in this process, developing a Next Generation Molecular Ecology . This research program will combine studies of candidate genes with large-scale gene expression analysis, several mapping approaches and comparative genomics to study the genetic basis of trait evolution in wild bird populations. First, we will search for and analyse loci involved with reproductive isolation and adaptive population divergence in a well-known system for speciation research the pied flycatcher and the collared flycatcher. A milestone of this program will be genome sequencing of the two flycatcher species. Second, we will track the genetic basis of behaviour using a unique breeding population of zebra finches and benefitting from the recently obtained genome sequence of this species. Third, we will identify the targets for adaptive evolution during avian evolution using comparative genomics. Overall, the program will be able to reveal the molecular genetic architecture behind phenotypic variation. The potential for scientific break-through in this interdisciplinary program should be significant.
Summary
There is an immediate need to increase our understanding of the genetic basis for fitness differences in natural populations (Ellegren and Sheldon Nature 452:169-175, 2008). Fortunately, technological developments within genome research, notably the recent ability to retrieve massive amounts of DNA sequence data based on next generation sequencing , will make possible completely novel investigations of the link between genotypes and phenotypes in non-model organisms. With our background as major players in molecular ecology and evolutionary genomics of non-models for the last 15-20 years, we are excellently placed to take on a leading role in this process, developing a Next Generation Molecular Ecology . This research program will combine studies of candidate genes with large-scale gene expression analysis, several mapping approaches and comparative genomics to study the genetic basis of trait evolution in wild bird populations. First, we will search for and analyse loci involved with reproductive isolation and adaptive population divergence in a well-known system for speciation research the pied flycatcher and the collared flycatcher. A milestone of this program will be genome sequencing of the two flycatcher species. Second, we will track the genetic basis of behaviour using a unique breeding population of zebra finches and benefitting from the recently obtained genome sequence of this species. Third, we will identify the targets for adaptive evolution during avian evolution using comparative genomics. Overall, the program will be able to reveal the molecular genetic architecture behind phenotypic variation. The potential for scientific break-through in this interdisciplinary program should be significant.
Max ERC Funding
2 500 000 €
Duration
Start date: 2010-04-01, End date: 2015-09-30
Project acronym NOVCAT
Project Design of Novel Catalysis by Metal Complexes
Researcher (PI) David Milstein
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Advanced Grant (AdG), PE5, ERC-2009-AdG
Summary Global concerns regarding the economy, environment and sustainable energy resources dictate an urgent need for the design of novel catalytic reactions. We have recently discovered novel, environmentally benign reactions catalyzed by pincer complexes, including an entirely new reaction, namely the direct coupling of alcohols with amines to produce amides and H2 (Science, 2007, 317, 790). We believe that the mechanisms of these reactions involve a new concept in catalysis: metal-ligand cooperation by aromatization-dearomatization of the ligand. Such cooperation can play key roles also in the activation of H2, C-H, and other bonds. Remarkably, we have very recently discovered a new strategy towards light-induced water splitting into H2 and O2, also based on metal-ligand cooperation in a pincer system, and have observed an unprecedented O-O bond formation process (Science, in press). The design of efficient catalytic systems for splitting water into hydrogen and oxygen, driven by sunlight, and without use of sacrificial reagents, is among the most important challenges facing science today, underpinning the potential of hydrogen as a clean, sustainable fuel. In this context, it is essential to enhance our understanding of the fundamental chemical steps involved in such processes. We plan to (a) explore the scope of bond activation and catalysis based on the new concept of metal ligand cooperation by aromatization-dearomatization (b) study the mechanism and scope of the newly discovered novel approach towards water splitting by light (c) develop novel environmentally benign catalytic reactions involving O-H, C-H and other bonds, such as anti-Markovnikov hydration of alkenes (d) develop unprecedented asymmetric catalysis using chiral cooperating ligands (e) develop new CO2 chemistry, including its hydrogenation to methanol and photolytic splitting to CO and O2. The research is expected to lead to novel catalysis, of importance to environment and sustainable energy.
Summary
Global concerns regarding the economy, environment and sustainable energy resources dictate an urgent need for the design of novel catalytic reactions. We have recently discovered novel, environmentally benign reactions catalyzed by pincer complexes, including an entirely new reaction, namely the direct coupling of alcohols with amines to produce amides and H2 (Science, 2007, 317, 790). We believe that the mechanisms of these reactions involve a new concept in catalysis: metal-ligand cooperation by aromatization-dearomatization of the ligand. Such cooperation can play key roles also in the activation of H2, C-H, and other bonds. Remarkably, we have very recently discovered a new strategy towards light-induced water splitting into H2 and O2, also based on metal-ligand cooperation in a pincer system, and have observed an unprecedented O-O bond formation process (Science, in press). The design of efficient catalytic systems for splitting water into hydrogen and oxygen, driven by sunlight, and without use of sacrificial reagents, is among the most important challenges facing science today, underpinning the potential of hydrogen as a clean, sustainable fuel. In this context, it is essential to enhance our understanding of the fundamental chemical steps involved in such processes. We plan to (a) explore the scope of bond activation and catalysis based on the new concept of metal ligand cooperation by aromatization-dearomatization (b) study the mechanism and scope of the newly discovered novel approach towards water splitting by light (c) develop novel environmentally benign catalytic reactions involving O-H, C-H and other bonds, such as anti-Markovnikov hydration of alkenes (d) develop unprecedented asymmetric catalysis using chiral cooperating ligands (e) develop new CO2 chemistry, including its hydrogenation to methanol and photolytic splitting to CO and O2. The research is expected to lead to novel catalysis, of importance to environment and sustainable energy.
Max ERC Funding
1 912 018 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym NOVEL TOOLS IN PD
Project Novel tools for real time monitoring and quantification of protein aggregation in Parkinson s disease and related neurodegenerative disorders
Researcher (PI) Hilal Lashuel
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary To understand the molecular basis of any biological process, it is critical that one is not only able to visualize and monitor molecular events that underlie this process, but also to possess the tools to manipulate these events in a spatial and temporal fashion both in and out of the cell. The overall objective of this proposal is to apply chemical biology approaches to allow real time monitoring of protein aggregation and to dissect the role of specific disease-associated post-translational modifications, phosphorylation, nitration, and truncation on the structure, aggregation, and biochemical properties of monomeric a-syn in health and disease. To achieve these goals, we plan to use a combination of organic chemistry, molecular biology, proteomics, protein engineering, and semisynthetic strategies to facilitate site-specific introduction of post-translational modifications that can be masked and activated in a controllable manner, both inside and outside living cells. Modified synthetic ±-syn will be introduced into primary neurons and cellular models of synucleinopathies and the consequences of masking or activating specific modifications will be assessed using biochemical, immunofluorescence, and live imaging techniques (Specific Aim 1). The absence of specific molecular probes that allow in vivo monitoring and quantitative measurement of toxic misfolded and aggregation intermediates represents a major impediment to understanding the relationship among protein misfolding, post-translational modification, protein aggregation, neurodegeneration, and cell death in PD and other neurodegenerative disorders. To address this challenge, we plan to develop and characterize novel antibodies that target different species along the amyloid formation pathway of ±-syn (Specific Aim 2).
Summary
To understand the molecular basis of any biological process, it is critical that one is not only able to visualize and monitor molecular events that underlie this process, but also to possess the tools to manipulate these events in a spatial and temporal fashion both in and out of the cell. The overall objective of this proposal is to apply chemical biology approaches to allow real time monitoring of protein aggregation and to dissect the role of specific disease-associated post-translational modifications, phosphorylation, nitration, and truncation on the structure, aggregation, and biochemical properties of monomeric a-syn in health and disease. To achieve these goals, we plan to use a combination of organic chemistry, molecular biology, proteomics, protein engineering, and semisynthetic strategies to facilitate site-specific introduction of post-translational modifications that can be masked and activated in a controllable manner, both inside and outside living cells. Modified synthetic ±-syn will be introduced into primary neurons and cellular models of synucleinopathies and the consequences of masking or activating specific modifications will be assessed using biochemical, immunofluorescence, and live imaging techniques (Specific Aim 1). The absence of specific molecular probes that allow in vivo monitoring and quantitative measurement of toxic misfolded and aggregation intermediates represents a major impediment to understanding the relationship among protein misfolding, post-translational modification, protein aggregation, neurodegeneration, and cell death in PD and other neurodegenerative disorders. To address this challenge, we plan to develop and characterize novel antibodies that target different species along the amyloid formation pathway of ±-syn (Specific Aim 2).
Max ERC Funding
1 495 400 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym NOWIRE
Project Network Coding for Wireless Networks
Researcher (PI) Christina Fragouli
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), PE7, ERC-2009-StG
Summary Our goal is to develop fundamentally new architectures for wireless networks that offer the convenience of wireless communication while achieving the performance, predictability and security of wired networks. The wireless channel is inherently a shared medium characterized by limited resources and complex signal interactions between transmitted signals. The question we address is how do we transmit information over wireless and how do we exploit the wireless channel properties to share its resources. Ours is a fundamentally different approach to existing strategies, that builds on new physical and packet layer sharing and cooperation paradigms that we have been working on, to extract the optimal throughput and reliability performance from the wireless medium. These are recent breakthroughs in (i) network coding and (ii) wireless cooperation. Network coding is a new area bringing a novel paradigm for network information flow that enables cooperation at a packet level to optimally share the network resources. Deployment of the first network coding ideas in wireless have already indicated benefits as large as a factor of ten in terms of throughput. Complex signal interactions caused by the inherent broadcast nature of wireless channels, is traditionally viewed as an impediment to be mitigated. Recently it has been demonstrated that one can utilize interference to develop cooperation at the wireless signal level (physical layer) for arbitrary wireless networks. This can give significant capacity advantages over techniques that mitigate interference. Both these ideas can radically affect the way information is communicated, stored and collected, and can revolutionize the design of future wireless networks. In this project we plan to addess several fundamental questions that develop on these themes. We take a complete view of these ideas by not only developing the underlying theory but also through validation on wireless testbeds.
Summary
Our goal is to develop fundamentally new architectures for wireless networks that offer the convenience of wireless communication while achieving the performance, predictability and security of wired networks. The wireless channel is inherently a shared medium characterized by limited resources and complex signal interactions between transmitted signals. The question we address is how do we transmit information over wireless and how do we exploit the wireless channel properties to share its resources. Ours is a fundamentally different approach to existing strategies, that builds on new physical and packet layer sharing and cooperation paradigms that we have been working on, to extract the optimal throughput and reliability performance from the wireless medium. These are recent breakthroughs in (i) network coding and (ii) wireless cooperation. Network coding is a new area bringing a novel paradigm for network information flow that enables cooperation at a packet level to optimally share the network resources. Deployment of the first network coding ideas in wireless have already indicated benefits as large as a factor of ten in terms of throughput. Complex signal interactions caused by the inherent broadcast nature of wireless channels, is traditionally viewed as an impediment to be mitigated. Recently it has been demonstrated that one can utilize interference to develop cooperation at the wireless signal level (physical layer) for arbitrary wireless networks. This can give significant capacity advantages over techniques that mitigate interference. Both these ideas can radically affect the way information is communicated, stored and collected, and can revolutionize the design of future wireless networks. In this project we plan to addess several fundamental questions that develop on these themes. We take a complete view of these ideas by not only developing the underlying theory but also through validation on wireless testbeds.
Max ERC Funding
1 771 520 €
Duration
Start date: 2009-09-01, End date: 2014-08-31
Project acronym OPTELOMAC
Project Opto-Electronic Organic Materials by New Acetylene Chemistry
Researcher (PI) Francois Nico Diederich
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Advanced Grant (AdG), PE5, ERC-2009-AdG
Summary "Atom-economic, atom-economic (""click""-type)transformations of donor (N,N-dialkylaniline, TTF, ferrocene)-activated acetylenes with strong electron-accepting olefins (TCNE, TCNQ, tricyanovinyl derivatives) are applied to the construction of stable molecular and supramolecular chromophores with unusual electronic and optical properties. Their properties are characterized in interdisciplinary collaboration with the objectives to provide new classes of chromophores for opto-electronic device applications, to investigate pi-electron delocalization in acetylenic molecular architectures extending into one, two, and three dimensions, and to advance fundamental knowledge in an interplay between experiment and theory allowing prediction and tuning of opto-electronic properties. Specific aims are: 1. New "super-electron acceptors" and investigation of their intra- and intermolecular charge-transfer interactions. These non-planar, stable, and sublimable chromophores are expected to possess high third-order optical nonlinearities and are investigated for formation of amorphous, high-optical quality films and conductive or magnetic charge-transfer complexes and salts with various electron donors. 2. Optically pure alleno-acetylenic macrocycles and oligomers adopting helical conformations. The chiroptical properties of these chromophores are exceptional and will be further enhanced in supramolecular assemblies. 3. Covalently modified fullerenes with increased electron uptake capability for applications in photovoltaic devices. 4. Regular [AB]-type oligomers and polymers using the formation of charge-transfer chromophores from acetylenic precursors as the chain-propagation step. 5. Zwitterionic, redox-amphiphilic dendrimers for mono- and multi-layer formation in organic electronic devices."
Summary
"Atom-economic, atom-economic (""click""-type)transformations of donor (N,N-dialkylaniline, TTF, ferrocene)-activated acetylenes with strong electron-accepting olefins (TCNE, TCNQ, tricyanovinyl derivatives) are applied to the construction of stable molecular and supramolecular chromophores with unusual electronic and optical properties. Their properties are characterized in interdisciplinary collaboration with the objectives to provide new classes of chromophores for opto-electronic device applications, to investigate pi-electron delocalization in acetylenic molecular architectures extending into one, two, and three dimensions, and to advance fundamental knowledge in an interplay between experiment and theory allowing prediction and tuning of opto-electronic properties. Specific aims are: 1. New "super-electron acceptors" and investigation of their intra- and intermolecular charge-transfer interactions. These non-planar, stable, and sublimable chromophores are expected to possess high third-order optical nonlinearities and are investigated for formation of amorphous, high-optical quality films and conductive or magnetic charge-transfer complexes and salts with various electron donors. 2. Optically pure alleno-acetylenic macrocycles and oligomers adopting helical conformations. The chiroptical properties of these chromophores are exceptional and will be further enhanced in supramolecular assemblies. 3. Covalently modified fullerenes with increased electron uptake capability for applications in photovoltaic devices. 4. Regular [AB]-type oligomers and polymers using the formation of charge-transfer chromophores from acetylenic precursors as the chain-propagation step. 5. Zwitterionic, redox-amphiphilic dendrimers for mono- and multi-layer formation in organic electronic devices."
Max ERC Funding
1 690 200 €
Duration
Start date: 2010-03-01, End date: 2015-02-28
Project acronym ORGELNANOCARBMATER
Project A Universal Supramolecular Approach toward Organic Electronic Materials and Nanostructured Carbonaceous Materials from Molecular Precursors
Researcher (PI) Holger Frauenrath
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), PE5, ERC-2009-StG
Summary Research in novel energy sources, efficient energy storage, sustainable chemical technology, and smaller microelectronic devices with interfaces for biological systems are among the current challenges in science and technology. Carbonaceous materials and organic electronic materials which speak the language of biomaterials will play a central role in the search for possible solutions. We aim to develop a universal supramolecular approach for their preparation and propose to develop synthetic pathways toward conjugated oligomers carrying hydrogen-bonded substituents, such as oligopeptide-polymer conjugates. These substituents serve as a supramolecular motif promoting the aggregation of the molecular precursors into single crystals, thin films, or soluble one-dimensional nanostructures. The obtained ordered phases or nanostructures from conjugated molecules themselves are highly interesting candidates for applications in photovoltaic, light-emitting, or semiconducting devices. Related nanostructures from oligo(phenylene)s or oligo(ethynylene)s will serve as reactive molecular precursors for a conversion into soluble graphene ribbon nanostructures. Finally, this approach will be extended toward the preparation of carbonaceous materials from amphiphilic oligo(ethynylene)s as energy-rich molecular precursors under preservation of the mesoscopic morphology, surface chemistry, and carbon microstructure. The obtained materials are highly interesting with respect to ion or hydrogen storage, and transition-metal-free catalysis. Hence, this research project aims to combine synthetic organic chemistry, supramolecular chemistry, and materials science in order to both deliver novel materials and improve our understanding in utilizing supramolecular-synthetic methods in their preparation.
Summary
Research in novel energy sources, efficient energy storage, sustainable chemical technology, and smaller microelectronic devices with interfaces for biological systems are among the current challenges in science and technology. Carbonaceous materials and organic electronic materials which speak the language of biomaterials will play a central role in the search for possible solutions. We aim to develop a universal supramolecular approach for their preparation and propose to develop synthetic pathways toward conjugated oligomers carrying hydrogen-bonded substituents, such as oligopeptide-polymer conjugates. These substituents serve as a supramolecular motif promoting the aggregation of the molecular precursors into single crystals, thin films, or soluble one-dimensional nanostructures. The obtained ordered phases or nanostructures from conjugated molecules themselves are highly interesting candidates for applications in photovoltaic, light-emitting, or semiconducting devices. Related nanostructures from oligo(phenylene)s or oligo(ethynylene)s will serve as reactive molecular precursors for a conversion into soluble graphene ribbon nanostructures. Finally, this approach will be extended toward the preparation of carbonaceous materials from amphiphilic oligo(ethynylene)s as energy-rich molecular precursors under preservation of the mesoscopic morphology, surface chemistry, and carbon microstructure. The obtained materials are highly interesting with respect to ion or hydrogen storage, and transition-metal-free catalysis. Hence, this research project aims to combine synthetic organic chemistry, supramolecular chemistry, and materials science in order to both deliver novel materials and improve our understanding in utilizing supramolecular-synthetic methods in their preparation.
Max ERC Funding
1 700 000 €
Duration
Start date: 2009-09-01, End date: 2014-08-31
Project acronym OXLEET
Project Oxidation via low-energy electron transfer. Development of green oxidation methodology via a biomimetic approach
Researcher (PI) Jan Erling Baeckvall
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), PE5, ERC-2009-AdG
Summary Oxidation reactions are of fundamental importance in Nature and are key transformation in organic synthesis. There is currently a need from society to replace waste-producing expensive oxidants by environmentally benign oxidants in industrial oxidation reactions. The aim with the proposed research is to develop novel green oxidation methodology that also involves hydrogen transfer reactions. In the oxidation reactions the goal is to use molecular oxygen (air) or hydrogen peroxide as the oxidants. In the present project new catalytic oxidations via low-energy electron transfer will be developed. The catalytic reactions obtained can be used for racemization of alcohols and amines and for oxygen- and hydrogen peroxide-driven oxidations of various substrates. Examples of some reactions that will be studied are oxidative palladium-catalyzed C-C bond formation and metal-catalyzed C-H oxidation including dehydrogenation reactions with iron and ruthenium. Coupled catalytic systems where electron transfer mediators (ETMs) facilitate electron transfer from the reduced catalyst to molecular oxygen (hydrogen peroxide) will be studied. Highly efficient reoxidation systems will be designed by covalently linking two electron transfer mediators (ETMs). The intramolecular electron transfer in these hybrid ETM catalysts will significantly increase the rate of oxidation reactions. The research will lead to development of more efficient reoxidation systems based on molecular oxygen and hydrogen peroxide, as well as more versatile racemization catalysts for alcohols and amines.
Summary
Oxidation reactions are of fundamental importance in Nature and are key transformation in organic synthesis. There is currently a need from society to replace waste-producing expensive oxidants by environmentally benign oxidants in industrial oxidation reactions. The aim with the proposed research is to develop novel green oxidation methodology that also involves hydrogen transfer reactions. In the oxidation reactions the goal is to use molecular oxygen (air) or hydrogen peroxide as the oxidants. In the present project new catalytic oxidations via low-energy electron transfer will be developed. The catalytic reactions obtained can be used for racemization of alcohols and amines and for oxygen- and hydrogen peroxide-driven oxidations of various substrates. Examples of some reactions that will be studied are oxidative palladium-catalyzed C-C bond formation and metal-catalyzed C-H oxidation including dehydrogenation reactions with iron and ruthenium. Coupled catalytic systems where electron transfer mediators (ETMs) facilitate electron transfer from the reduced catalyst to molecular oxygen (hydrogen peroxide) will be studied. Highly efficient reoxidation systems will be designed by covalently linking two electron transfer mediators (ETMs). The intramolecular electron transfer in these hybrid ETM catalysts will significantly increase the rate of oxidation reactions. The research will lead to development of more efficient reoxidation systems based on molecular oxygen and hydrogen peroxide, as well as more versatile racemization catalysts for alcohols and amines.
Max ERC Funding
1 722 000 €
Duration
Start date: 2010-01-01, End date: 2015-12-31
Project acronym PAC
Project Proofs and Computation
Researcher (PI) Eliyahu Ben Sasson
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Country Israel
Call Details Starting Grant (StG), PE6, ERC-2009-StG
Summary The project described in this proposal studies formal proofs and their interaction with computation. The study of propositional proofs is connected to a spectrum of problems in our field, starting with the meta-mathematical quest to explain our failure to understand computation and make progress on the basic questions haunting our field (such as P vs. NP), and ending with the industry-driven quest for better algorithms for solving instances of the satisfiability problem. In a seemingly different direction, the recent introduction of magical probabilistically checkable proofs (PCPs) has opened new horizons in computer science, ranging from a deeper understanding of approximation algorithms and their limits to the construction of super-efficient protocols for the verification of proofs and computations. We suggest to study proofs and computation with three main objectives. First, to construct better SAT solvers via a better understanding of propositional proof systems. Second, to expand the range of applications of PCPs and transform them from the purely theoretical objects that they currently are to practical and accessible formats for use in all settings where proofs are encountered. Third, to expand our theoretical understanding of the intrinsic limits of proofs, with an eye towards explaining why we are unable to make significant progress on central questions in computational complexity. We believe this project can bridge across different regions of computer science such as SAT solving and proof complexity, theory and practice, propositional proofs and probabilistically checkable ones. And its expected impact will start on the theoretical mathematical level that forms the foundation of computer science and percolate to more practical areas of our field.
Summary
The project described in this proposal studies formal proofs and their interaction with computation. The study of propositional proofs is connected to a spectrum of problems in our field, starting with the meta-mathematical quest to explain our failure to understand computation and make progress on the basic questions haunting our field (such as P vs. NP), and ending with the industry-driven quest for better algorithms for solving instances of the satisfiability problem. In a seemingly different direction, the recent introduction of magical probabilistically checkable proofs (PCPs) has opened new horizons in computer science, ranging from a deeper understanding of approximation algorithms and their limits to the construction of super-efficient protocols for the verification of proofs and computations. We suggest to study proofs and computation with three main objectives. First, to construct better SAT solvers via a better understanding of propositional proof systems. Second, to expand the range of applications of PCPs and transform them from the purely theoretical objects that they currently are to practical and accessible formats for use in all settings where proofs are encountered. Third, to expand our theoretical understanding of the intrinsic limits of proofs, with an eye towards explaining why we are unable to make significant progress on central questions in computational complexity. We believe this project can bridge across different regions of computer science such as SAT solving and proof complexity, theory and practice, propositional proofs and probabilistically checkable ones. And its expected impact will start on the theoretical mathematical level that forms the foundation of computer science and percolate to more practical areas of our field.
Max ERC Funding
1 743 676 €
Duration
Start date: 2009-12-01, End date: 2015-09-30
Project acronym PALMASSEMBLY
Project Protein assembly: From the molecular scale to the mesoscale with super-resolution imaging
Researcher (PI) Suliana Manley
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), LS1, ERC-2009-StG
Summary Cellular responses to external signals begin at the plasma membrane, where the dynamic assembly of receptors can regulate cellular activity. Membrane-enveloped viruses, including the human immunodeficiency virus (HIV) also assemble at the plasma membrane, exploiting mechanisms evolved for cellular trafficking. However, our physical paradigm for how proteins form mesoscale assemblies is far from complete. While the organization and dynamics of membrane proteins are heterogeneous, commonly used fluorescence-based measurements lack information at the molecular scale. In contrast, single molecule measurements limited to looking at only a few molecules in a given cell lack ensemble information. Thus, the study of protein assembly has been limited by a lack of spatially resolved, dynamic information on ensembles of molecules. We will use super-resolution fluorescence imaging techniques combined with live cell imaging and single molecule tracking to determine how the dynamics of protein assembly are coordinated. The long-term goal of my research is to use quantitative fluorescence methods to identify the physical mechanisms for protein transport and organization in cells. The objective of this proposal is to establish quantitative models of protein assembly in two specific biological systems which were selected for the distinct characteristics of their assembly, and their relevance to human health. This will test the central hypothesis that molecular assembly is enhanced by the organization of the plasma membrane in the form of cytoskeletal elements and protein-lipid platforms. This interdisciplinary research will provide an experimental foundation for a statistical description of the cell, whose behaviour is embedded in protein organization and dynamics.
Summary
Cellular responses to external signals begin at the plasma membrane, where the dynamic assembly of receptors can regulate cellular activity. Membrane-enveloped viruses, including the human immunodeficiency virus (HIV) also assemble at the plasma membrane, exploiting mechanisms evolved for cellular trafficking. However, our physical paradigm for how proteins form mesoscale assemblies is far from complete. While the organization and dynamics of membrane proteins are heterogeneous, commonly used fluorescence-based measurements lack information at the molecular scale. In contrast, single molecule measurements limited to looking at only a few molecules in a given cell lack ensemble information. Thus, the study of protein assembly has been limited by a lack of spatially resolved, dynamic information on ensembles of molecules. We will use super-resolution fluorescence imaging techniques combined with live cell imaging and single molecule tracking to determine how the dynamics of protein assembly are coordinated. The long-term goal of my research is to use quantitative fluorescence methods to identify the physical mechanisms for protein transport and organization in cells. The objective of this proposal is to establish quantitative models of protein assembly in two specific biological systems which were selected for the distinct characteristics of their assembly, and their relevance to human health. This will test the central hypothesis that molecular assembly is enhanced by the organization of the plasma membrane in the form of cytoskeletal elements and protein-lipid platforms. This interdisciplinary research will provide an experimental foundation for a statistical description of the cell, whose behaviour is embedded in protein organization and dynamics.
Max ERC Funding
1 542 518 €
Duration
Start date: 2009-12-01, End date: 2015-11-30
Project acronym PARADIGM
Project New Paradigm in the Design of Degradable Polymeric Materials - Macroscopic Performance Translated to all Levels of Order
Researcher (PI) Ann-Christine Albertsson
Host Institution (HI) KUNGLIGA TEKNISKA HOEGSKOLAN
Country Sweden
Call Details Advanced Grant (AdG), PE8, ERC-2009-AdG
Summary A new generation of polymeric materials is needed promptly that does not behave like traditional commodity plastics in terms of environmental interaction, degradation pattern, fragmentation tendency, and biological persistency. I herein propose a new paradigm in the design of polymeric materials; the design of polymeric materials through a retro-structural approach where the macroscopic performance is translated to every scale level of structural order so that appropriate molecular recognitions are identified and subsequently synthetically generated in a bottom-up procedure. Inspiration on how to design such materials is best drawn from Nature which is unsurpassed in its ability to combine molecular building blocks into perfectly designed versatile super- and supramolecular structures with well-defined properties, disassembly patterns, and biological functions. A closer look into the structural build-up of biological materials gives important clues on how to design synthetic functional materials with desirable environmental interaction. In addition to advanced synthesis, surface modification and processing, the materials and their degradation behavior will be thoroughly characterized by using traditional characterization techniques in combination with latest spectroscopic and imaging techniques. I have chosen to focus on two areas that stand out as highly prioritized in maintaining or even raising our quality of life; sustainable materials for commodity applications and tissue engineering systems in biomaterials science. This is a bold high risk proposal which if successful will have a ground-breaking influence on how we design polymeric materials.
Summary
A new generation of polymeric materials is needed promptly that does not behave like traditional commodity plastics in terms of environmental interaction, degradation pattern, fragmentation tendency, and biological persistency. I herein propose a new paradigm in the design of polymeric materials; the design of polymeric materials through a retro-structural approach where the macroscopic performance is translated to every scale level of structural order so that appropriate molecular recognitions are identified and subsequently synthetically generated in a bottom-up procedure. Inspiration on how to design such materials is best drawn from Nature which is unsurpassed in its ability to combine molecular building blocks into perfectly designed versatile super- and supramolecular structures with well-defined properties, disassembly patterns, and biological functions. A closer look into the structural build-up of biological materials gives important clues on how to design synthetic functional materials with desirable environmental interaction. In addition to advanced synthesis, surface modification and processing, the materials and their degradation behavior will be thoroughly characterized by using traditional characterization techniques in combination with latest spectroscopic and imaging techniques. I have chosen to focus on two areas that stand out as highly prioritized in maintaining or even raising our quality of life; sustainable materials for commodity applications and tissue engineering systems in biomaterials science. This is a bold high risk proposal which if successful will have a ground-breaking influence on how we design polymeric materials.
Max ERC Funding
2 500 000 €
Duration
Start date: 2010-03-01, End date: 2016-02-29
Project acronym PDECP
Project Partial differential equations of Classical Physics
Researcher (PI) Demetrios Christodoulou
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Advanced Grant (AdG), PE1, ERC-2009-AdG
Summary I shall pursue two projects both of which belong to the fields of partial differential equations, geometric analysis and mathematical physics. The first project, ``the shock development problem", belongs also to the field of fluid dynamics and aims at a full understanding of how, in the real world of 3 spatial dimensions, hydrodynamic shocks evolve, my previous work having analyzed in detail how they form. The second project, ``the formation of electromagnetic shocks in nonlinear media" aims at establishing how electromagnetic shocks form by the focusing of incoming electromagnetic wave pulses in a nonlinear medium. The case of an isotropic nonlinear dielectric will be studied first, to be followed by the case of a general isotropic medium. The methods of geometric analysis introduced in my previous work shall be employed, in particular the ``short pulse method" introduced in my work on the formation of black holes by the focusing of incoming gravitational waves in general relativity. The application of these methods to the problem for a general isotropic medium will require the development of new geometric structures. My three Ph. D. students shall purse the following three projects, belonging also to the fields of partial differential equations, geometric analysis and mathematical physics. The first project is in nonlinear elasticity. It is the study of the equilibrium configurations, in free space, of a crystalline solid in which a continuous distribution of dislocations is present, and aims at analyzing the relationship between the dislocation distribution and the resulting internal stress field. The second is in general relativity and aims at a theoretical understanding of the phenomena discovered by M. Choptuik in his numerical study of the gravitational collapse of a self-gravitating scalar field in spherical symmetry. The third is the study of hydrodynamic shock interactions and focusing in spherical symmetry.
Summary
I shall pursue two projects both of which belong to the fields of partial differential equations, geometric analysis and mathematical physics. The first project, ``the shock development problem", belongs also to the field of fluid dynamics and aims at a full understanding of how, in the real world of 3 spatial dimensions, hydrodynamic shocks evolve, my previous work having analyzed in detail how they form. The second project, ``the formation of electromagnetic shocks in nonlinear media" aims at establishing how electromagnetic shocks form by the focusing of incoming electromagnetic wave pulses in a nonlinear medium. The case of an isotropic nonlinear dielectric will be studied first, to be followed by the case of a general isotropic medium. The methods of geometric analysis introduced in my previous work shall be employed, in particular the ``short pulse method" introduced in my work on the formation of black holes by the focusing of incoming gravitational waves in general relativity. The application of these methods to the problem for a general isotropic medium will require the development of new geometric structures. My three Ph. D. students shall purse the following three projects, belonging also to the fields of partial differential equations, geometric analysis and mathematical physics. The first project is in nonlinear elasticity. It is the study of the equilibrium configurations, in free space, of a crystalline solid in which a continuous distribution of dislocations is present, and aims at analyzing the relationship between the dislocation distribution and the resulting internal stress field. The second is in general relativity and aims at a theoretical understanding of the phenomena discovered by M. Choptuik in his numerical study of the gravitational collapse of a self-gravitating scalar field in spherical symmetry. The third is the study of hydrodynamic shock interactions and focusing in spherical symmetry.
Max ERC Funding
1 278 000 €
Duration
Start date: 2010-03-01, End date: 2015-02-28
Project acronym PLANETOGENESIS
Project Building the next generation of planet formation models: protoplanetary disks, internal structure, and formation of planetary systems
Researcher (PI) Yann Alibert
Host Institution (HI) UNIVERSITAET BERN
Country Switzerland
Call Details Starting Grant (StG), PE9, ERC-2009-StG
Summary The discovery of extra-solar planetary systems with properties so different from those of our own Solar System has overturned our theoretical understanding of how planets and planetary systems form. Indeed, planet formation models have to link observations of two classes of objects: Protoplanetary disk, whose structure and early evolution provide the initial conditions of planets formation, and actual detected planets. The observational knowledge of these two classes of objects will see in the near future dramatic improvements, with three major breakthroughs: 1) high angular resolution observations will tightly constrain the structure and early evolution of protoplanetary disks, 2) direct observation of extrasolar planets will allow to understand their internal structure as well as their formation process, and 3) detection of very low mass extrasolar planets will constrain the mass function of planets and planetary systems, down to the terrestrial planet regime The goal of this project is to develop a theoretical understanding of planet formation that quantitatively stands up to these observational confrontations. For this, we will build on the basis of first generation planet formation models developed at the time the PI was assistant at the Physikalisches Institute of the University of Berne. The PI, a PhD student, and a Postdoc will conduct three inter-related sub-projects linked to the three breakthroughs mentioned above: A) improving the disk part of planet formation models, B) determining the internal structure of forming planets, including the effects of accretion shocks and envelope pollution by infalling planetesimals, and calculating their early evolution, and C) building planetary system formation models, including both gas giant and low mass rocky planets.
Summary
The discovery of extra-solar planetary systems with properties so different from those of our own Solar System has overturned our theoretical understanding of how planets and planetary systems form. Indeed, planet formation models have to link observations of two classes of objects: Protoplanetary disk, whose structure and early evolution provide the initial conditions of planets formation, and actual detected planets. The observational knowledge of these two classes of objects will see in the near future dramatic improvements, with three major breakthroughs: 1) high angular resolution observations will tightly constrain the structure and early evolution of protoplanetary disks, 2) direct observation of extrasolar planets will allow to understand their internal structure as well as their formation process, and 3) detection of very low mass extrasolar planets will constrain the mass function of planets and planetary systems, down to the terrestrial planet regime The goal of this project is to develop a theoretical understanding of planet formation that quantitatively stands up to these observational confrontations. For this, we will build on the basis of first generation planet formation models developed at the time the PI was assistant at the Physikalisches Institute of the University of Berne. The PI, a PhD student, and a Postdoc will conduct three inter-related sub-projects linked to the three breakthroughs mentioned above: A) improving the disk part of planet formation models, B) determining the internal structure of forming planets, including the effects of accretion shocks and envelope pollution by infalling planetesimals, and calculating their early evolution, and C) building planetary system formation models, including both gas giant and low mass rocky planets.
Max ERC Funding
1 395 323 €
Duration
Start date: 2010-02-01, End date: 2015-11-30
Project acronym PRIONS
Project The prion protein in health and disease
Researcher (PI) Adriano Aguzzi
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Advanced Grant (AdG), LS5, ERC-2009-AdG
Summary Oligomers are toxic in an array of protein misfolding and aggregation (PMA) disorders. However, the chain of events from protein aggregation to dysfunction is poorly understood. Prion diseases are marked by accumulation of PrPSc, a misfolded variant of wild-type PrPC. PrPC mediates PrPSc neurotoxicity and counteracts toxic PrPC mutants, indicating that a subversion of normal PrPC function may underlie neurodegeneration, and this may not be limited to prion disease. Here, we propose to explore these newly discovered physiological functions of PrPC in three paradigms. We show that PrPC assembles into a multiprotein complex containing a protease; neurotoxic PrPC mutants generate a smaller complex that is uncleaved. We show that neuronal expression of PrPC is required in trans for long-term myelin maintenance in peripheral nerves. We will therefore investigate the hypothesis that a fragment of PrPC transmits signals crucial for axomyelinic integrity. We show that PrPC physically interacts with both amyloid b and islet amyloid polypeptide and attenuates functional impairment mediated by these peptides. We therefore propose to test whether subversion of normal PrPC function is involved in diverse PMA disorders. We developed an ex vivo model that accurately reproduces major features of prion infections, most notably neurodegeneration. We have identified several unexpected PrPSc-induced cellular stress pathways which may be common to other PMA disorders. Using this model system, we will clarify the role of PrPC in cell survival pathways and determine the requirement for PrPC in the pathology of other PMA disorders. This proposal capitalizes on provocative recent results and, if successful, will provide valuable insights into PMA toxicity that will go far beyond prion diseases.
Summary
Oligomers are toxic in an array of protein misfolding and aggregation (PMA) disorders. However, the chain of events from protein aggregation to dysfunction is poorly understood. Prion diseases are marked by accumulation of PrPSc, a misfolded variant of wild-type PrPC. PrPC mediates PrPSc neurotoxicity and counteracts toxic PrPC mutants, indicating that a subversion of normal PrPC function may underlie neurodegeneration, and this may not be limited to prion disease. Here, we propose to explore these newly discovered physiological functions of PrPC in three paradigms. We show that PrPC assembles into a multiprotein complex containing a protease; neurotoxic PrPC mutants generate a smaller complex that is uncleaved. We show that neuronal expression of PrPC is required in trans for long-term myelin maintenance in peripheral nerves. We will therefore investigate the hypothesis that a fragment of PrPC transmits signals crucial for axomyelinic integrity. We show that PrPC physically interacts with both amyloid b and islet amyloid polypeptide and attenuates functional impairment mediated by these peptides. We therefore propose to test whether subversion of normal PrPC function is involved in diverse PMA disorders. We developed an ex vivo model that accurately reproduces major features of prion infections, most notably neurodegeneration. We have identified several unexpected PrPSc-induced cellular stress pathways which may be common to other PMA disorders. Using this model system, we will clarify the role of PrPC in cell survival pathways and determine the requirement for PrPC in the pathology of other PMA disorders. This proposal capitalizes on provocative recent results and, if successful, will provide valuable insights into PMA toxicity that will go far beyond prion diseases.
Max ERC Funding
2 500 000 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym PTPSBDC
Project The role of protein-tyrosine phosphatases in breast development and cancer
Researcher (PI) Mohamed Bentires-Alj
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Country Switzerland
Call Details Starting Grant (StG), LS4, ERC-2009-StG
Summary Each year 1.1 million new cases of breast cancer will occur among women worldwide and 400,000 women will die from this disease. Although progress has been made in understanding breast tumor biology, most of the relevant molecules and pathways remain undefined. Their delineation is critical to a rational approach to breast cancer therapy. This proposal focuses on the role of the under-explored family of protein-tyrosine phosphatases (PTPs) in the normal and neoplastic breast. Virtually all cell signaling pathways are modulated by reversible protein tyrosine phosphorylation, which is regulated by two classes of enzymes: protein-tyrosine kinases (PTKs) and PTPs. Not surprisingly, tyrosine phosphorylation has an important role in breast development and cancer. Whereas the role of specific PTKs, like the HER2 receptor, in breast cancer is well studied, almost nothing is known about the function of specific PTPs in this disease. Our preliminary data suggest that PTP1B has an important role in breast differentiation and that both PTP1B and SHP2 play positive roles in breast cancer. The two predominant goals of this proposal are: First, to delineate the role of PTP1B and other PTPs in normal breast development and differentiation; second, to address the roles of PTP1B and other PTPs in the maintenance of breast cancer and metastasis and to assess their merits as drug targets. These studies not only use state-of-the-art ex vivo and in vivo models for studying breast pathophysiology, but also cross the boundaries between the developmental and cancer research fields and between basic science and clinical applications. Our research should ultimately lead to the rational design of targeted therapies that will improve the clinical management of patients with breast cancer.
Summary
Each year 1.1 million new cases of breast cancer will occur among women worldwide and 400,000 women will die from this disease. Although progress has been made in understanding breast tumor biology, most of the relevant molecules and pathways remain undefined. Their delineation is critical to a rational approach to breast cancer therapy. This proposal focuses on the role of the under-explored family of protein-tyrosine phosphatases (PTPs) in the normal and neoplastic breast. Virtually all cell signaling pathways are modulated by reversible protein tyrosine phosphorylation, which is regulated by two classes of enzymes: protein-tyrosine kinases (PTKs) and PTPs. Not surprisingly, tyrosine phosphorylation has an important role in breast development and cancer. Whereas the role of specific PTKs, like the HER2 receptor, in breast cancer is well studied, almost nothing is known about the function of specific PTPs in this disease. Our preliminary data suggest that PTP1B has an important role in breast differentiation and that both PTP1B and SHP2 play positive roles in breast cancer. The two predominant goals of this proposal are: First, to delineate the role of PTP1B and other PTPs in normal breast development and differentiation; second, to address the roles of PTP1B and other PTPs in the maintenance of breast cancer and metastasis and to assess their merits as drug targets. These studies not only use state-of-the-art ex vivo and in vivo models for studying breast pathophysiology, but also cross the boundaries between the developmental and cancer research fields and between basic science and clinical applications. Our research should ultimately lead to the rational design of targeted therapies that will improve the clinical management of patients with breast cancer.
Max ERC Funding
1 571 365 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym PUSHBOUND
Project Pushing the Boundaries of Molecular Dynamics Simulations
Researcher (PI) Michele Parrinello
Host Institution (HI) UNIVERSITA DELLA SVIZZERA ITALIANA
Country Switzerland
Call Details Advanced Grant (AdG), PE4, ERC-2009-AdG
Summary Atomistic computer simulation has established itself as one of the most important methodologies in modern science, its impact being felt in areas as diverse as physics, chemistry, geophysics, materials science and biophysics, to name but a few. Yet in spite of great progress in computer power and algorithms, we are still not able to simulate such important phenomena as nucleation, phase transitions or protein folding. The purpose of this proposal is to strongly push back the limits of length, time scale and accuracy of present-day methods, greatly enhancing the scope of atomistic simulations. We expect the impact of a successful outcome of this proposal to revolutionize the field. We shall make use of three technical innovations: an extension of Langevin-type equations to include correlated (colored) noise; the use of h-matrices to speed up electronic structure calculations; and an intelligent use of neural networks. Our strategy will be complex. We plan to speed up ab-initio molecular dynamics calculations considerably and also to generate new and highly accurate effective potentials based on electronic structure calculations. A large part of our effort will be devoted to the time scale problem. In this respect we shall improve metadynamics so that its implementation becomes as general and as automatic as possible, and we shall also introduce methods for reconstructing the real dynamics from metadynamics. Finally, highly innovative and powerful sampling methods based on specially designed colored noise Langevin equations will be developed.
Summary
Atomistic computer simulation has established itself as one of the most important methodologies in modern science, its impact being felt in areas as diverse as physics, chemistry, geophysics, materials science and biophysics, to name but a few. Yet in spite of great progress in computer power and algorithms, we are still not able to simulate such important phenomena as nucleation, phase transitions or protein folding. The purpose of this proposal is to strongly push back the limits of length, time scale and accuracy of present-day methods, greatly enhancing the scope of atomistic simulations. We expect the impact of a successful outcome of this proposal to revolutionize the field. We shall make use of three technical innovations: an extension of Langevin-type equations to include correlated (colored) noise; the use of h-matrices to speed up electronic structure calculations; and an intelligent use of neural networks. Our strategy will be complex. We plan to speed up ab-initio molecular dynamics calculations considerably and also to generate new and highly accurate effective potentials based on electronic structure calculations. A large part of our effort will be devoted to the time scale problem. In this respect we shall improve metadynamics so that its implementation becomes as general and as automatic as possible, and we shall also introduce methods for reconstructing the real dynamics from metadynamics. Finally, highly innovative and powerful sampling methods based on specially designed colored noise Langevin equations will be developed.
Max ERC Funding
2 499 600 €
Duration
Start date: 2010-08-01, End date: 2015-07-31
Project acronym QUORUMPROBES
Project An Integrated Chemical Platform to Elucidate Eukaryotic Sensing of Bacterial Crosstalk
Researcher (PI) Michael Meijler
Host Institution (HI) BEN-GURION UNIVERSITY OF THE NEGEV
Country Israel
Call Details Starting Grant (StG), PE5, ERC-2009-StG
Summary The term quorum sensing (QS) describes the ability of a population of unicellular bacteria to act as a single multicellular organism in a cell-density-dependent manner. Bacteria achieve this feat by the use of small diffusible molecules to exchange information among themselves. Examples of QS-controlled behaviors are bioluminescence, virulence factor expression and biofilm formation. These processes are advantageous to a bacterial population only when they are carried out simultaneously by its members. In recent years, a surprising new role has been found for several QS molecules diverse eukaryotes have been found to react strongly to the presence of these compounds. My aim is to examine the hypothesis that diverse eukaryotic species have developed mechanisms to react to the presence of specific bacterial QS molecules in a receptor-mediated fashion. Specifically, we aim to identify receptors that are highly specific for the Pseudomonas aeruginosa QSM 3-oxo-C12-AHL, as no receptor has been identified yet. This is a significant challenge, that we will address developing an innovative platform of chemical, biochemical and microbiological investigations. Identification of specific QSM receptors in eukaryotes will allow us to further understand the complex mechanisms of coexistence and evolution of coexistence between prokaryotes and eukaryotes. The insight obtained from these experiments could lead to: a) an increased understanding of important principles that guide the evolution of symbiotic relationships between competing species; b) new approaches in the treatment of P. aeruginosa infections, as well as to potential new drugs for the treatment of autoimmune diseases; c) the development of an integrated platform that will enable the discovery of unknown receptors for small hydrophobic bioactive compounds.
Summary
The term quorum sensing (QS) describes the ability of a population of unicellular bacteria to act as a single multicellular organism in a cell-density-dependent manner. Bacteria achieve this feat by the use of small diffusible molecules to exchange information among themselves. Examples of QS-controlled behaviors are bioluminescence, virulence factor expression and biofilm formation. These processes are advantageous to a bacterial population only when they are carried out simultaneously by its members. In recent years, a surprising new role has been found for several QS molecules diverse eukaryotes have been found to react strongly to the presence of these compounds. My aim is to examine the hypothesis that diverse eukaryotic species have developed mechanisms to react to the presence of specific bacterial QS molecules in a receptor-mediated fashion. Specifically, we aim to identify receptors that are highly specific for the Pseudomonas aeruginosa QSM 3-oxo-C12-AHL, as no receptor has been identified yet. This is a significant challenge, that we will address developing an innovative platform of chemical, biochemical and microbiological investigations. Identification of specific QSM receptors in eukaryotes will allow us to further understand the complex mechanisms of coexistence and evolution of coexistence between prokaryotes and eukaryotes. The insight obtained from these experiments could lead to: a) an increased understanding of important principles that guide the evolution of symbiotic relationships between competing species; b) new approaches in the treatment of P. aeruginosa infections, as well as to potential new drugs for the treatment of autoimmune diseases; c) the development of an integrated platform that will enable the discovery of unknown receptors for small hydrophobic bioactive compounds.
Max ERC Funding
1 392 000 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym RECONMET
Project Reconstruction of methane flux from lakes: development and application of a new approach
Researcher (PI) Oliver Heiri
Host Institution (HI) UNIVERSITAET BERN
Country Switzerland
Call Details Starting Grant (StG), PE10, ERC-2009-StG
Summary Reconstruction of methane flux from lakes: development and application of a new approach
Summary
Reconstruction of methane flux from lakes: development and application of a new approach
Max ERC Funding
1 554 000 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym RMAC
Project RISK MANAGEMENT AFTER THE CRISIS
Researcher (PI) Jean-Charles Rochet
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Advanced Grant (AdG), SH1, ERC-2009-AdG
Summary The current financial crisis testifies that the sophisticated risk management models used by large financial institutions are inadequate. The main objective of this research project is to analyze the sources of this failure and to develop sound conceptual principles for founding new risk management methods for financial institutions. In spite of the wide use of sophisticated risk management models by the majority of large firms, the conceptual foundations for them are weak. Most of them rely on the assumption that financial markets always function well. The few theoretical models that incorporate endogenous financial frictions use contract theoretic tools but they are static or two period models. Such models cannot generate really testable implications, or provide quantitatively reasonable policy recommendations. Another strand of the theoretical literature has developed diffusion models for modelling the financial behaviour of corporations in continuous time. However this literature is mathematically oriented and makes very strong assumptions, without clear justifications. Our objective is to combine these two approaches and construct testable dynamic models with endogenous financial frictions. These models are to be simple enough that they can provide reasonable policy recommendations, with a particular attention to banks and insurance companies. By adapting the general model of corporate risk management in a dynamic set-up to the specificities of financial intermediaries, we will develop a model of risk management for the financial sector. Implications will be derived for prudential regulation of financial intermediaries and the organisation of supervision, with a particular attention to the prevention and management of future financial crises.
Summary
The current financial crisis testifies that the sophisticated risk management models used by large financial institutions are inadequate. The main objective of this research project is to analyze the sources of this failure and to develop sound conceptual principles for founding new risk management methods for financial institutions. In spite of the wide use of sophisticated risk management models by the majority of large firms, the conceptual foundations for them are weak. Most of them rely on the assumption that financial markets always function well. The few theoretical models that incorporate endogenous financial frictions use contract theoretic tools but they are static or two period models. Such models cannot generate really testable implications, or provide quantitatively reasonable policy recommendations. Another strand of the theoretical literature has developed diffusion models for modelling the financial behaviour of corporations in continuous time. However this literature is mathematically oriented and makes very strong assumptions, without clear justifications. Our objective is to combine these two approaches and construct testable dynamic models with endogenous financial frictions. These models are to be simple enough that they can provide reasonable policy recommendations, with a particular attention to banks and insurance companies. By adapting the general model of corporate risk management in a dynamic set-up to the specificities of financial intermediaries, we will develop a model of risk management for the financial sector. Implications will be derived for prudential regulation of financial intermediaries and the organisation of supervision, with a particular attention to the prevention and management of future financial crises.
Max ERC Funding
1 440 000 €
Duration
Start date: 2010-03-01, End date: 2016-02-29
Project acronym RWPERCRI
Project Random Walks, Percolation and Random Interlacements
Researcher (PI) Alain-Sol Sznitman
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Advanced Grant (AdG), PE1, ERC-2009-AdG
Summary The general theme of this research proposal involves random walks and percolation theory. The research proposal aims at exploring in depth the surprising links between on the one hand a class of problems directly pertaining to random walks (in particular related to disconnection, or the creation of large vacant components and separating interfaces), and on the other hand questions pertaining to a non-conventional model of percolation based on random interlacements. Traditional methods of percolation typically do not apply to this model. The present research program if successfull ought to uncover new paradigms and lead to the development of new methods.
Summary
The general theme of this research proposal involves random walks and percolation theory. The research proposal aims at exploring in depth the surprising links between on the one hand a class of problems directly pertaining to random walks (in particular related to disconnection, or the creation of large vacant components and separating interfaces), and on the other hand questions pertaining to a non-conventional model of percolation based on random interlacements. Traditional methods of percolation typically do not apply to this model. The present research program if successfull ought to uncover new paradigms and lead to the development of new methods.
Max ERC Funding
583 092 €
Duration
Start date: 2010-04-01, End date: 2014-03-31
Project acronym SEXGENTRANSEVOLUTION
Project Sex-biased genome and transcriptome evolution in mammals
Researcher (PI) Henrik Kaessmann
Host Institution (HI) UNIVERSITE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), LS2, ERC-2009-StG
Summary Mammalian males and females have many phenotypic differences. These differences, collectively referred to as sexual dimorphism, are the consequence of natural and sexual selection for phenotypic traits that affect the fitness of each sex and are encoded in the genome. Part of the underlying genomic differences between the sexes are found on sex specific (the Y) or sex biased chromosomes (the X), while many sexually dimorphic traits probably result from autosomal gene expression differences in sex specific or somatic tissues. However, the origin and evolution of sex-biased genes in mammals has not been studied in detail. I propose to generate the first detailed qualitative and quantitative transcriptome data using next generation sequencing technologies for a unique collection of germline and somatic tissues from representatives of all major mammalian lineages: placental mammals, marsupials, and the egg-laying monotremes. Together with detailed transcriptome data from birds (the evolutionary sister lineage), complementary experiments (e.g. methylome analyses), and available genomic resources from these species, these unprecedented data will allow an integrated analysis of the origin and functional evolution of mammalian sex chromosomes, the emergence of new sex biased genes, and the evolution of gene expression in germline versus somatic tissues in mammals at large. The proposed work will thus substantially increase our power to understand how mammalian genomes evolved the capacity to produce such pronounced sexually dimorphic traits. Beyond research pertaining to sex biased genome evolution, our data will represent a unique resource for future investigations of mammalian gene functions and serve as a basis for exploring the evolution of other mammal specific phenotypes.
Summary
Mammalian males and females have many phenotypic differences. These differences, collectively referred to as sexual dimorphism, are the consequence of natural and sexual selection for phenotypic traits that affect the fitness of each sex and are encoded in the genome. Part of the underlying genomic differences between the sexes are found on sex specific (the Y) or sex biased chromosomes (the X), while many sexually dimorphic traits probably result from autosomal gene expression differences in sex specific or somatic tissues. However, the origin and evolution of sex-biased genes in mammals has not been studied in detail. I propose to generate the first detailed qualitative and quantitative transcriptome data using next generation sequencing technologies for a unique collection of germline and somatic tissues from representatives of all major mammalian lineages: placental mammals, marsupials, and the egg-laying monotremes. Together with detailed transcriptome data from birds (the evolutionary sister lineage), complementary experiments (e.g. methylome analyses), and available genomic resources from these species, these unprecedented data will allow an integrated analysis of the origin and functional evolution of mammalian sex chromosomes, the emergence of new sex biased genes, and the evolution of gene expression in germline versus somatic tissues in mammals at large. The proposed work will thus substantially increase our power to understand how mammalian genomes evolved the capacity to produce such pronounced sexually dimorphic traits. Beyond research pertaining to sex biased genome evolution, our data will represent a unique resource for future investigations of mammalian gene functions and serve as a basis for exploring the evolution of other mammal specific phenotypes.
Max ERC Funding
1 901 522 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym SINGLE-CELL GENOMICS
Project Single-cell Gene Regulation in Differentiation and Pluripotency
Researcher (PI) Thore Rickard Hakan Sandberg
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Starting Grant (StG), LS2, ERC-2009-StG
Summary We aim to study transcriptomes with single-cell resolution, a long-standing goal in biology, to answer fundamental questions about gene regulation. The main objective concerns gene regulation during in vivo differentiation and in pluripotent cells by studying single-cells from murine preimplantation embryos, a model system with natural single-cell resolution, important biology and medical potential. This would also allow us to explore general regulatory principles of gene expression programs of individual cells. This research program will be accomplished by novel deep sequencing technology of mRNAs (mRNA-Seq) to obtain quantitative, unbiased and genome-wide gene and isoform expression measurements. We are therefore developing new experimental and computational methods for genome-wide analyses of transcriptomes at single-cell resolution. The biological significances of the proposed research are unique insights into early embryonic development. Deep sequencing of transcriptomes will also reveal post-transcriptional gene regulation important for pluripotent cells and identified pluripotency-specific gene and isoform expressions will be important for future stem cell based therapies. The inherit single-cell nature of the model system together with its important biology makes it a model systems exceptionally well suited for a systems biology approach aiming to characterize gene regulation at single-cell resolution. The novel methodology has tremendous potential to enable complete mRNA characterization of individual cells. The deep sequencing approach with state-of-the-art computational analyses is both more quantitative than previous methods and it will give readouts on alternative isoforms generated by alternative promoters, splicing and polyadenylation.
Summary
We aim to study transcriptomes with single-cell resolution, a long-standing goal in biology, to answer fundamental questions about gene regulation. The main objective concerns gene regulation during in vivo differentiation and in pluripotent cells by studying single-cells from murine preimplantation embryos, a model system with natural single-cell resolution, important biology and medical potential. This would also allow us to explore general regulatory principles of gene expression programs of individual cells. This research program will be accomplished by novel deep sequencing technology of mRNAs (mRNA-Seq) to obtain quantitative, unbiased and genome-wide gene and isoform expression measurements. We are therefore developing new experimental and computational methods for genome-wide analyses of transcriptomes at single-cell resolution. The biological significances of the proposed research are unique insights into early embryonic development. Deep sequencing of transcriptomes will also reveal post-transcriptional gene regulation important for pluripotent cells and identified pluripotency-specific gene and isoform expressions will be important for future stem cell based therapies. The inherit single-cell nature of the model system together with its important biology makes it a model systems exceptionally well suited for a systems biology approach aiming to characterize gene regulation at single-cell resolution. The novel methodology has tremendous potential to enable complete mRNA characterization of individual cells. The deep sequencing approach with state-of-the-art computational analyses is both more quantitative than previous methods and it will give readouts on alternative isoforms generated by alternative promoters, splicing and polyadenylation.
Max ERC Funding
1 654 384 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym SIRAID
Project SIRT6 activation for countering age-related metabolic diseases
Researcher (PI) Haim Cohen
Host Institution (HI) BAR ILAN UNIVERSITY
Country Israel
Call Details Starting Grant (StG), LS4, ERC-2009-StG
Summary The significant increase in the human lifespan during the last century confronts us with great medical challenges. To answer them, one must understand and control the mechanisms that determine the rate of ageing. The sirtuins, and in particular the mammalian member SIRT6, are a family of NAD+ dependent deacetylases that were implicated in ageing and the regulation of metabolism. Much evidence correlates SIRT6 with the regulation of ageing, primarily the manifestation of ageing related pathologies in SIRT6 deficient mice, and the induction of SIRT6 by calorie-restricted diet that delays ageing and reduces its related diseases. Nonetheless, the role of SIRT6 in ageing and the mechanisms by which it might act are still elusive. To explore it at the molecular mechanistic level, SIRAID aims to i) study the role of SIRT6 in glucose and fat metabolism under high fat diet; ii) to determine whether SIRT6 is involved in regulating life span, and to characterise how SIRT6 is activated by calorie restriction; and iii) to perform large scale SILAC-based proteomics screening for SIRT6 substrates. These results will then be used for the development of small activator molecules of SIRT6 that may be used therapeutically for age related metabolic diseases. Taken together, we suggest a multifaceted approach that will allow us to explore the role of SIRT6 in ageing and metabolism, and to translate this knowledge to counter and prevent the medical problems associated with human longevity.
Summary
The significant increase in the human lifespan during the last century confronts us with great medical challenges. To answer them, one must understand and control the mechanisms that determine the rate of ageing. The sirtuins, and in particular the mammalian member SIRT6, are a family of NAD+ dependent deacetylases that were implicated in ageing and the regulation of metabolism. Much evidence correlates SIRT6 with the regulation of ageing, primarily the manifestation of ageing related pathologies in SIRT6 deficient mice, and the induction of SIRT6 by calorie-restricted diet that delays ageing and reduces its related diseases. Nonetheless, the role of SIRT6 in ageing and the mechanisms by which it might act are still elusive. To explore it at the molecular mechanistic level, SIRAID aims to i) study the role of SIRT6 in glucose and fat metabolism under high fat diet; ii) to determine whether SIRT6 is involved in regulating life span, and to characterise how SIRT6 is activated by calorie restriction; and iii) to perform large scale SILAC-based proteomics screening for SIRT6 substrates. These results will then be used for the development of small activator molecules of SIRT6 that may be used therapeutically for age related metabolic diseases. Taken together, we suggest a multifaceted approach that will allow us to explore the role of SIRT6 in ageing and metabolism, and to translate this knowledge to counter and prevent the medical problems associated with human longevity.
Max ERC Funding
1 510 968 €
Duration
Start date: 2009-10-01, End date: 2014-09-30
Project acronym SMARTDRUGENTITIES
Project Sophisticated Well-Targeted Therapeutic Entities based on Biologically Compatible Ti(IV) Active Cores and Building Blocks
Researcher (PI) Edit Tshuva (Goldberg)
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Starting Grant (StG), PE5, ERC-2009-StG
Summary I propose to develop sophisticated anti-tumor agents targeted particularly to the location of activity. My team has recently introduced a new family of Ti(IV) complexes that demonstrates higher activity than known compounds with substantially higher stability and defined hydrolytic behavior, properties that were found to be essential. I propose to study various derivatives and identify the parameters affecting activity, including steric and electronic effects, enantiomeric purity, ligand lability etc., and elucidation various mechanistic aspects of reactivity. More importantly, I propose to construct pH-sensitive transport units that will allow protection of the sensitive active species throughout their delivery and release only near the target location based on the variable pH conditions of different human tissues. In particular, unique spherical molecules held together by metal-ligand interactions will be prepared. The building blocks will consist of the planar ligands of C3-axis bound to three biocompatible Ti(IV) ions each with defined angles and geometry. The resulting spherical compounds will be utilized to encapsulate the active complexes and release them upon hydrolysis at the desired pH based on the pH-dependent hydrolysis pattern already established for related compounds. Preliminary calculations have confirmed the possibility of forming these compounds, which are particularly matching in their expected size to encapsulate our complexes. Larger spheres will also be prepared as cavities for larger molecules, which may be linked together for the delivery of multiple drugs. These compounds may find applications in various areas where a protected environment or delivery of sensitive compounds is required, such as in gene therapy, nano-technology, and catalysis.
Summary
I propose to develop sophisticated anti-tumor agents targeted particularly to the location of activity. My team has recently introduced a new family of Ti(IV) complexes that demonstrates higher activity than known compounds with substantially higher stability and defined hydrolytic behavior, properties that were found to be essential. I propose to study various derivatives and identify the parameters affecting activity, including steric and electronic effects, enantiomeric purity, ligand lability etc., and elucidation various mechanistic aspects of reactivity. More importantly, I propose to construct pH-sensitive transport units that will allow protection of the sensitive active species throughout their delivery and release only near the target location based on the variable pH conditions of different human tissues. In particular, unique spherical molecules held together by metal-ligand interactions will be prepared. The building blocks will consist of the planar ligands of C3-axis bound to three biocompatible Ti(IV) ions each with defined angles and geometry. The resulting spherical compounds will be utilized to encapsulate the active complexes and release them upon hydrolysis at the desired pH based on the pH-dependent hydrolysis pattern already established for related compounds. Preliminary calculations have confirmed the possibility of forming these compounds, which are particularly matching in their expected size to encapsulate our complexes. Larger spheres will also be prepared as cavities for larger molecules, which may be linked together for the delivery of multiple drugs. These compounds may find applications in various areas where a protected environment or delivery of sensitive compounds is required, such as in gene therapy, nano-technology, and catalysis.
Max ERC Funding
1 400 000 €
Duration
Start date: 2009-10-01, End date: 2014-09-30
Project acronym SOCIAL LIFE
Project The evolution of social life and division of labour
Researcher (PI) Laurent Keller
Host Institution (HI) UNIVERSITE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), LS8, ERC-2009-AdG
Summary The hallmark of social insect colonies is reproductive division of labour which is often associated with dramatic morphological and behavioural differences between queens, workers and males. The aim of this proposal is three-fold. First, we will use our recently developed fiducial identification system to investigate the general principles of social organisation and division of labour. The video tracking of workers labelled with markers derived from the augmented reality library ARTag allows us for the first time to distinguish up to 2000 individuals and precisely locate them every 500ms, hence allowing large-scale experiments addressing the question of how the behaviour of individual workers is influenced by the joint effects of environmental factors and social interactions. The second related aim is to investigate how the level of altruism within colonies and the reliability of communication systems are shaped by colony kin structure. Because it is not possible to conduct artificial evolution with social insects we will use a new experimental system consisting of colonies of small mobile robots with simple vision and communication abilities. This system permits to conduct hundreds of generations of experimental evolution in colonies with variable group composition to identify the factors affecting the evolution of altruism and communication. Finally, we will complement these studies with a genetic perspective using a remarkable genetic social polymorphism that we recently discovered in the fire ant Solenopsis invicta. The advent of new ultra high-throughput sequencing techniques will allow us to document the steps involved in the evolution of this genetic social polymorphism and test the suggestion that the chromosome involved in the social polymorphism has the properties of a sex chromosome. This project will be highly interdisciplinary, involving skills in evolutionary biology, the study of animal behaviour, bioinformatics, engineering and molecular biology
Summary
The hallmark of social insect colonies is reproductive division of labour which is often associated with dramatic morphological and behavioural differences between queens, workers and males. The aim of this proposal is three-fold. First, we will use our recently developed fiducial identification system to investigate the general principles of social organisation and division of labour. The video tracking of workers labelled with markers derived from the augmented reality library ARTag allows us for the first time to distinguish up to 2000 individuals and precisely locate them every 500ms, hence allowing large-scale experiments addressing the question of how the behaviour of individual workers is influenced by the joint effects of environmental factors and social interactions. The second related aim is to investigate how the level of altruism within colonies and the reliability of communication systems are shaped by colony kin structure. Because it is not possible to conduct artificial evolution with social insects we will use a new experimental system consisting of colonies of small mobile robots with simple vision and communication abilities. This system permits to conduct hundreds of generations of experimental evolution in colonies with variable group composition to identify the factors affecting the evolution of altruism and communication. Finally, we will complement these studies with a genetic perspective using a remarkable genetic social polymorphism that we recently discovered in the fire ant Solenopsis invicta. The advent of new ultra high-throughput sequencing techniques will allow us to document the steps involved in the evolution of this genetic social polymorphism and test the suggestion that the chromosome involved in the social polymorphism has the properties of a sex chromosome. This project will be highly interdisciplinary, involving skills in evolutionary biology, the study of animal behaviour, bioinformatics, engineering and molecular biology
Max ERC Funding
2 497 500 €
Duration
Start date: 2010-05-01, End date: 2016-04-30
Project acronym SOFTGROWTH
Project Growth and Shaping of Soft Tissue
Researcher (PI) Eran Sharon
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Starting Grant (StG), PE5, ERC-2009-StG
Summary Many natural structures are made of soft tissue that undergoes complicated continuous shape transformations that accurately and reliably serve specific elaborate tasks. Such processes can be slow, as in growth of a tissue, leading from an initial, featureless, shape to the desired elaborate structure of the adult organ. In other cases continuous shape transformations of soft tissue are rapid and are used for the production of mechanical work, as in the case of the action of the hart. Our understanding of natural growth is limited and our ability to produce controlled motions of soft tissue is poor. A central problem in both cases is how to incorporate all local changes in the tissue in order to determine the mechanical state of the entire body. In addition, there are problems regarding how to measure a deforming body and how to characterize the deformation. Finally, there is a problem of how to control motion and growth in artificial and natural soft tissues. I propose a multi disciplinary study, based on an approach I have started developing. According to it there is an underlying common mathematical way to describe continuous large shape transformations of stretchable tissues. This approach clearly defines the way to determine the mechanical state of a deformed tissue and to measure its local growth/deformation. The project will involve a theoretical study within mechanics and differential geometry, an experimental-physics work, which will be focused on the construction of responsive deformable tissue elements and measurements of their shape evolution, and a biophysical work, in which the natural growth and motion of leaves will be measured and will be correlated with biological activities. Such an integrative study has the potential of advancing our understanding of the fascinating process of growth and to improve our ability to construct bio-inspired "soft machinery".
Summary
Many natural structures are made of soft tissue that undergoes complicated continuous shape transformations that accurately and reliably serve specific elaborate tasks. Such processes can be slow, as in growth of a tissue, leading from an initial, featureless, shape to the desired elaborate structure of the adult organ. In other cases continuous shape transformations of soft tissue are rapid and are used for the production of mechanical work, as in the case of the action of the hart. Our understanding of natural growth is limited and our ability to produce controlled motions of soft tissue is poor. A central problem in both cases is how to incorporate all local changes in the tissue in order to determine the mechanical state of the entire body. In addition, there are problems regarding how to measure a deforming body and how to characterize the deformation. Finally, there is a problem of how to control motion and growth in artificial and natural soft tissues. I propose a multi disciplinary study, based on an approach I have started developing. According to it there is an underlying common mathematical way to describe continuous large shape transformations of stretchable tissues. This approach clearly defines the way to determine the mechanical state of a deformed tissue and to measure its local growth/deformation. The project will involve a theoretical study within mechanics and differential geometry, an experimental-physics work, which will be focused on the construction of responsive deformable tissue elements and measurements of their shape evolution, and a biophysical work, in which the natural growth and motion of leaves will be measured and will be correlated with biological activities. Such an integrative study has the potential of advancing our understanding of the fascinating process of growth and to improve our ability to construct bio-inspired "soft machinery".
Max ERC Funding
1 000 000 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym SPARSAM
Project Sparse Sampling: Theory, Algorithms and Applications
Researcher (PI) Martin Vetterli
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), PE7, ERC-2009-AdG
Summary Signal representations with Fourier and wavelet bases are central to signal processing and communications. Non-linear approximation methods in such bases are key for problems like denoising, compression and inverse problems. Recently, the idea that signals that are sparse in some domain can be acquired at low sampling density has generated strong interest, under various names like compressed sensing, compressive sampling and sparse sampling. We aim to study the central problem of acquiring continuous-time signals for discrete-time processing and reconstruction using the methods of sparse sampling. Solving this involves developing theory and algorithms for sparse sampling, both in continuous and discrete time. In addition, in order to acquire physical signals, we plan to develop a sampling theory for signals obeying physical laws, like the wave and diffusion equation, and light fields. Together, this will lead to a sparse sampling theory and framework for signal processing and communications, with applications from analog-to-digital conversion to new compression methods, to super-resolution data acquisition and to inverse problems in imaging. In sum, we aim to develop the theory and algorithms for sparse signal processing, with impact on a broad range of applications.
Summary
Signal representations with Fourier and wavelet bases are central to signal processing and communications. Non-linear approximation methods in such bases are key for problems like denoising, compression and inverse problems. Recently, the idea that signals that are sparse in some domain can be acquired at low sampling density has generated strong interest, under various names like compressed sensing, compressive sampling and sparse sampling. We aim to study the central problem of acquiring continuous-time signals for discrete-time processing and reconstruction using the methods of sparse sampling. Solving this involves developing theory and algorithms for sparse sampling, both in continuous and discrete time. In addition, in order to acquire physical signals, we plan to develop a sampling theory for signals obeying physical laws, like the wave and diffusion equation, and light fields. Together, this will lead to a sparse sampling theory and framework for signal processing and communications, with applications from analog-to-digital conversion to new compression methods, to super-resolution data acquisition and to inverse problems in imaging. In sum, we aim to develop the theory and algorithms for sparse signal processing, with impact on a broad range of applications.
Max ERC Funding
1 839 174 €
Duration
Start date: 2010-05-01, End date: 2015-04-30
Project acronym SQMS
Project Synthetic Quantum Many-Body Systems
Researcher (PI) Tilman Holger Esslinger
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Advanced Grant (AdG), PE2, ERC-2009-AdG
Summary This proposal shows a new path to explore frontiers in quantum many-body physics using degenerate atomic gases. We will address fundamental open questions, create novel quantum-many body systems and seek applications beyond the realm of quantum gases. A two-component Fermi gas in an optical lattice is a unique realisation of the Fermi-Hubbard model and it is intimately linked to elementary concepts and open questions in many-body physics. We will develop novel tools for continuous cooling and detection of fermionic atoms in optical lattices. This will enable us to enter the anti-ferromagnetic phase and to study fundamental questions concerning the interplay between localization, coherence and spin-ordering in quantum many-body systems. An intriguing direction towards the creation of novel quantum many-body systems is the coupling of a strongly correlated quantum gas to an optical cavity. Here the cavity creates an effective long-range interaction with global character. This will bring together the physics of strongly-correlated systems and non-linear phenomena using a microscopically accessible system. In this highly explorative field we envisage, as a first experiment, a study of cavity-driven self-organization which may allow us to identify a novel form of a supersolid phase. Rather than investigating or manipulating the quantum gas using light we will also invert this approach and study the light after the interaction with a quantum gas inside a cavity. Using cavity opto-mechanical effects and a van der-Waals blockade by Rydberg atoms excited inside the cavity we will explore squeezing of the light and a novel photon blockade.
Summary
This proposal shows a new path to explore frontiers in quantum many-body physics using degenerate atomic gases. We will address fundamental open questions, create novel quantum-many body systems and seek applications beyond the realm of quantum gases. A two-component Fermi gas in an optical lattice is a unique realisation of the Fermi-Hubbard model and it is intimately linked to elementary concepts and open questions in many-body physics. We will develop novel tools for continuous cooling and detection of fermionic atoms in optical lattices. This will enable us to enter the anti-ferromagnetic phase and to study fundamental questions concerning the interplay between localization, coherence and spin-ordering in quantum many-body systems. An intriguing direction towards the creation of novel quantum many-body systems is the coupling of a strongly correlated quantum gas to an optical cavity. Here the cavity creates an effective long-range interaction with global character. This will bring together the physics of strongly-correlated systems and non-linear phenomena using a microscopically accessible system. In this highly explorative field we envisage, as a first experiment, a study of cavity-driven self-organization which may allow us to identify a novel form of a supersolid phase. Rather than investigating or manipulating the quantum gas using light we will also invert this approach and study the light after the interaction with a quantum gas inside a cavity. Using cavity opto-mechanical effects and a van der-Waals blockade by Rydberg atoms excited inside the cavity we will explore squeezing of the light and a novel photon blockade.
Max ERC Funding
2 000 000 €
Duration
Start date: 2010-03-01, End date: 2015-02-28
Project acronym STAHDPDE
Project Sparse Tensor Approximations of High-Dimensional and stochastic Partial Differential Equations
Researcher (PI) Christoph Buchs-Schwab
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Advanced Grant (AdG), PE1, ERC-2009-AdG
Summary The present project addresses numerical analysis and algorithmic realization of sparse, adaptive tensor product discretizations of partial differential equations (PDEs) in high dimensions with stochastic data. The aim of the project is to develop mathematically founded adaptive algorithms which are based on sparse tensorization of hierarchic Riesz bases or frames. These will be hierarchic multilevel bases in the physical domain, either Finite Element wavelet type bases or hierarchical, multilevel bases. In the parameter domains corresponding either to random inputs or to phase spaces in transport problems, spectral type representations of ``polynomial chaos'' type shall be employed. Mathematical aim is to analyzed for a classes of elliptic and parabolic PDEs on high or possibly infinite dimensional parameter spaces adaptive, deterministic and dimension independent solution methods with convergence rates superior to those afforded by Monte Carlo Methods, in terms of accuracy vs. complexity. Algorithmic work will address design of data structures with minimal overhead for the efficient realization of the sparse tensor approximations. Applications include space-time adaptive solvers for elliptic, parabolic and certain parametric hyperbolic PDEs, nonlinear approximate spectral representations of nonstationary random fields, scale-resolving solvers of elliptic and parabolic problems with multiple scales with complexity independent of the number of scales, and sparse, adaptive numerical solvers for parametric transport problems. The project will be in collaboration with coworkers in France, Germany, UK, The Netherlands. The project involves mentoring postdocs and predocs who will be actively involved in all aspects of the research, as well as a teaching component.
Summary
The present project addresses numerical analysis and algorithmic realization of sparse, adaptive tensor product discretizations of partial differential equations (PDEs) in high dimensions with stochastic data. The aim of the project is to develop mathematically founded adaptive algorithms which are based on sparse tensorization of hierarchic Riesz bases or frames. These will be hierarchic multilevel bases in the physical domain, either Finite Element wavelet type bases or hierarchical, multilevel bases. In the parameter domains corresponding either to random inputs or to phase spaces in transport problems, spectral type representations of ``polynomial chaos'' type shall be employed. Mathematical aim is to analyzed for a classes of elliptic and parabolic PDEs on high or possibly infinite dimensional parameter spaces adaptive, deterministic and dimension independent solution methods with convergence rates superior to those afforded by Monte Carlo Methods, in terms of accuracy vs. complexity. Algorithmic work will address design of data structures with minimal overhead for the efficient realization of the sparse tensor approximations. Applications include space-time adaptive solvers for elliptic, parabolic and certain parametric hyperbolic PDEs, nonlinear approximate spectral representations of nonstationary random fields, scale-resolving solvers of elliptic and parabolic problems with multiple scales with complexity independent of the number of scales, and sparse, adaptive numerical solvers for parametric transport problems. The project will be in collaboration with coworkers in France, Germany, UK, The Netherlands. The project involves mentoring postdocs and predocs who will be actively involved in all aspects of the research, as well as a teaching component.
Max ERC Funding
1 349 564 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym STATECAP
Project State Capacity, Development, Conflict, and Climate Change
Researcher (PI) Torsten Erik Persson
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), SH1, ERC-2009-AdG
Summary The proposed research concerns two sets of issues. The first concerns the role of state building in the development process, and the role played by violent conflict whether internal or external to the state. In this research, we will build a sequence of theoretical models, taking a stepping stone in a basic framework where new infrastructure that expands the state s capacity to raise revenue and to support private markets is viewed as outcome of investments under uncertainty. Our objective in model building is to provide guidance for the collection of historical and contemporary data and for econometric testing, which will both be central to the project. The overall goal of this project is to bring the analysis of state capacity into the mainstream of economics, and thereby shed light on the complex interactions between state building, conflict and development. The second set of issues ultimately concerns the economics of climate change. A first subproject aims at estimating the historical effects of weather on infant mortality in Africa, using a variety of data sources: individual data based on retrospective DHS surveys, finely-gridded weather data based on so-called re-analyis with large-scale climate models, and spatial data on harvest times based on satellite data on plant growth. Exploiting the random component of historical weather fluctuation allows us to estimate causal effects on health outcomes via mechanisms like malnutrition and malaria. This initial research will serve as a pilot study, to develop a methodology for studying the weather impacts on any outcome of interest anywhere in the world. Eventually such estimates will serve to estimate the future costs of climate change.
Summary
The proposed research concerns two sets of issues. The first concerns the role of state building in the development process, and the role played by violent conflict whether internal or external to the state. In this research, we will build a sequence of theoretical models, taking a stepping stone in a basic framework where new infrastructure that expands the state s capacity to raise revenue and to support private markets is viewed as outcome of investments under uncertainty. Our objective in model building is to provide guidance for the collection of historical and contemporary data and for econometric testing, which will both be central to the project. The overall goal of this project is to bring the analysis of state capacity into the mainstream of economics, and thereby shed light on the complex interactions between state building, conflict and development. The second set of issues ultimately concerns the economics of climate change. A first subproject aims at estimating the historical effects of weather on infant mortality in Africa, using a variety of data sources: individual data based on retrospective DHS surveys, finely-gridded weather data based on so-called re-analyis with large-scale climate models, and spatial data on harvest times based on satellite data on plant growth. Exploiting the random component of historical weather fluctuation allows us to estimate causal effects on health outcomes via mechanisms like malnutrition and malaria. This initial research will serve as a pilot study, to develop a methodology for studying the weather impacts on any outcome of interest anywhere in the world. Eventually such estimates will serve to estimate the future costs of climate change.
Max ERC Funding
1 489 744 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym STRONGPCP
Project Strong Probabilistically Checkable Proofs
Researcher (PI) Irit Dveer Dinur
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Starting Grant (StG), PE6, ERC-2009-StG
Summary Probabilistically Checkable Proofs (PCPs) encapsulate the striking idea that verification of proofs becomes nearly trivial if one is willing to use randomness. The PCP theorem, proven in the early 90's, is a cornerstone of modern computational complexity theory. It completely revises our notion of a proof, leading to an amazingly robust behavior: A PCP proof is guaranteed to have an abundance of errors if attempting to prove a falsity. This stands in sharp contrast to our classical notion of a proof whose correctness can collapse due to one wrong step. An important drive in the development of PCP theory is the revolutionary effect it had on the field of approximation. Feige et. al. [JACM, 1996] discovered that the PCP theorem is *equivalent* to the inapproximability of several classical optimization problems. Thus, PCP theory has resulted in a leap in our understanding of approximability and opened the gate to a flood of results. To date, virtually all inapproximability results are based on the PCP theorem, and while there is an impressive body of work on hardness-of-approximation, much work still lies ahead. The central goal of this proposal is to obtain stronger PCPs than currently known, leading towards optimal inapproximability results and novel notions of robustness in computation and in proofs. This study will build upon (i) new directions opened up by my novel proof of the PCP theorem [JACM, 2007]; and on (ii) state-of-the-art PCP machinery involving techniques from algebra, functional and harmonic analysis, probability, combinatorics, and coding theory. The broader impact of this study spans a better understanding of limits for approximation algorithms saving time and resources for algorithm designers; and new understanding of robustness in a variety of mathematical contexts, arising from the many connections between PCPs and stability questions in combinatorics, functional analysis, metric embeddings, probability, and more.
Summary
Probabilistically Checkable Proofs (PCPs) encapsulate the striking idea that verification of proofs becomes nearly trivial if one is willing to use randomness. The PCP theorem, proven in the early 90's, is a cornerstone of modern computational complexity theory. It completely revises our notion of a proof, leading to an amazingly robust behavior: A PCP proof is guaranteed to have an abundance of errors if attempting to prove a falsity. This stands in sharp contrast to our classical notion of a proof whose correctness can collapse due to one wrong step. An important drive in the development of PCP theory is the revolutionary effect it had on the field of approximation. Feige et. al. [JACM, 1996] discovered that the PCP theorem is *equivalent* to the inapproximability of several classical optimization problems. Thus, PCP theory has resulted in a leap in our understanding of approximability and opened the gate to a flood of results. To date, virtually all inapproximability results are based on the PCP theorem, and while there is an impressive body of work on hardness-of-approximation, much work still lies ahead. The central goal of this proposal is to obtain stronger PCPs than currently known, leading towards optimal inapproximability results and novel notions of robustness in computation and in proofs. This study will build upon (i) new directions opened up by my novel proof of the PCP theorem [JACM, 2007]; and on (ii) state-of-the-art PCP machinery involving techniques from algebra, functional and harmonic analysis, probability, combinatorics, and coding theory. The broader impact of this study spans a better understanding of limits for approximation algorithms saving time and resources for algorithm designers; and new understanding of robustness in a variety of mathematical contexts, arising from the many connections between PCPs and stability questions in combinatorics, functional analysis, metric embeddings, probability, and more.
Max ERC Funding
1 639 584 €
Duration
Start date: 2009-09-01, End date: 2016-06-30
Project acronym SYSTEAM
Project Systems and Signals Tools for Estimation and Analysis of Mathematical Models in Endocrinology and Neurology
Researcher (PI) Peter Stoica
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), PE7, ERC-2009-AdG
Summary This proposal envisages a research program in the field of systems and signals that will lead to innovative and agile mathematical modeling as well as model-based signal processing and control tools for applications in biology and medicine. The project's goal is to bridge the gap between systems biology, on one hand, and medical signal processing and control engineering, on the other. Mathematical models of systems biology will be used to devise algorithms for biological data processing and computerized medical interventions. Experimental biological and clinical data will be utilized to estimate and characterize the parameters of mathematical models derived for biological phenomena and mechanisms. An extensive collaboration network of medical researchers from Sweden and abroad will provide the project team with necessary experimental data as well as with access to medical competence. The envisaged tools are expected to be applicable more generally but their efficacy will be demonstrated in two main application areas. These areas are endocrinology and neurology for which the use of formal control engineering and signal processing methods is currently deemed to be most promising. The proposed program will result in novel systems and signals tools for medical research and health care enabling multi-input multi-output modeling and analysis of endocrine regulations and providing model-based algorithms for individualized drug dose titration.
Summary
This proposal envisages a research program in the field of systems and signals that will lead to innovative and agile mathematical modeling as well as model-based signal processing and control tools for applications in biology and medicine. The project's goal is to bridge the gap between systems biology, on one hand, and medical signal processing and control engineering, on the other. Mathematical models of systems biology will be used to devise algorithms for biological data processing and computerized medical interventions. Experimental biological and clinical data will be utilized to estimate and characterize the parameters of mathematical models derived for biological phenomena and mechanisms. An extensive collaboration network of medical researchers from Sweden and abroad will provide the project team with necessary experimental data as well as with access to medical competence. The envisaged tools are expected to be applicable more generally but their efficacy will be demonstrated in two main application areas. These areas are endocrinology and neurology for which the use of formal control engineering and signal processing methods is currently deemed to be most promising. The proposed program will result in novel systems and signals tools for medical research and health care enabling multi-input multi-output modeling and analysis of endocrine regulations and providing model-based algorithms for individualized drug dose titration.
Max ERC Funding
2 379 000 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym TERRAINCOGNITA
Project T cell receptor αβ : in control of signal initiation and T cell fate
Researcher (PI) Ed Palmer
Host Institution (HI) UNIVERSITATSSPITAL BASEL
Country Switzerland
Call Details Advanced Grant (AdG), LS6, ERC-2009-AdG
Summary One of the central mysteries of immunology is self-tolerance. How does the human body select ~10e12 T lymphocytes, that are reactive to foreign pathogens but tolerant to normal cellular constituents of the host? Over the last few years, my laboratory identified 2 fundamental mechanisms used by thymocytes to establish T cell tolerance. We demonstrated that the affinity threshold for negative selection is a constant for all thymocytes expressing MHC I restricted TCRs. This binding affinity threshold (KD H 6 ¼M; estimated T1/2 H 2 sec) is the fundamental biophysical parameter used by TCRs to delete autoimmune T cells. We also established how the TCR generates distinct signals for positive and negative selection. At the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signaling intermediates. The ability to compartmentalize signaling molecules differentially within the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the molecular basis for central tolerance. In the present application, we plan to fully understand 1-how the biophysical events during antigen binding to the TCR initiate an intracellular signal; 2-how these signals program an unambiguous cell fate and 3-how the system fails, when an autoimmune T cell is generated and activated. We will use a combination of transgenic and knockout mice, biochemistry and molecular imaging to fully define how the TCR functions as a molecular switch.
Summary
One of the central mysteries of immunology is self-tolerance. How does the human body select ~10e12 T lymphocytes, that are reactive to foreign pathogens but tolerant to normal cellular constituents of the host? Over the last few years, my laboratory identified 2 fundamental mechanisms used by thymocytes to establish T cell tolerance. We demonstrated that the affinity threshold for negative selection is a constant for all thymocytes expressing MHC I restricted TCRs. This binding affinity threshold (KD H 6 ¼M; estimated T1/2 H 2 sec) is the fundamental biophysical parameter used by TCRs to delete autoimmune T cells. We also established how the TCR generates distinct signals for positive and negative selection. At the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signaling intermediates. The ability to compartmentalize signaling molecules differentially within the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the molecular basis for central tolerance. In the present application, we plan to fully understand 1-how the biophysical events during antigen binding to the TCR initiate an intracellular signal; 2-how these signals program an unambiguous cell fate and 3-how the system fails, when an autoimmune T cell is generated and activated. We will use a combination of transgenic and knockout mice, biochemistry and molecular imaging to fully define how the TCR functions as a molecular switch.
Max ERC Funding
1 930 000 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym TIMESIGNAL
Project Signalling within the mammalian circadian timing system
Researcher (PI) Ulrich Schibler
Host Institution (HI) UNIVERSITE DE GENEVE
Country Switzerland
Call Details Advanced Grant (AdG), LS1, ERC-2009-AdG
Summary The main objective of this interdisciplinary research project is to elucidate regulatory mechanisms through which the circadian timing system coordinates temporal physiology. This system has a hierarchical architecture, in that a master clock in the brain s suprachiasmatic nucleus synchronizes subsidiary oscillators in nearly all body cells. The establishment of phase coherence is obviously of utmost importance in the coordination of circadian physiology. While recent studies have identified feeding cycles, hormone rhythms, and body temperature oscillations as timing cues for peripheral clocks, the molecular makeup of the involved signalling mechanisms is largely unknown. Using liver and cultured cells as model systems, we will employ two innovative strategies for the elucidation of relevant signalling pathways. (1) STAR-Prom (Synthetic TAndem Repeat-PROmoter display), a technique developed in our laboratory, will hopefully identify most if not all immediate early transcription factors activated in cultured cells by rhythmic blood-borne and temperature-dependent signals. (2) A transgenic mouse model with conditionally active liver clocks will be explored in the genome-wide identification of coding and non-coding transcripts whose rhythmic accumulation is system-driven. The in vivo significance of the components emerging from these approaches will be assessed via RNA interference. Thus, relevant siRNAs will be injected into the tail vein of mice, and their effect on the phase of circadian liver gene expression will be monitored in freely moving mice by using whole body fluorescence imaging. Physiologically important components will serve as entry points for the identification of upstream and downstream constituents in the corresponding signal transduction cascades.
Summary
The main objective of this interdisciplinary research project is to elucidate regulatory mechanisms through which the circadian timing system coordinates temporal physiology. This system has a hierarchical architecture, in that a master clock in the brain s suprachiasmatic nucleus synchronizes subsidiary oscillators in nearly all body cells. The establishment of phase coherence is obviously of utmost importance in the coordination of circadian physiology. While recent studies have identified feeding cycles, hormone rhythms, and body temperature oscillations as timing cues for peripheral clocks, the molecular makeup of the involved signalling mechanisms is largely unknown. Using liver and cultured cells as model systems, we will employ two innovative strategies for the elucidation of relevant signalling pathways. (1) STAR-Prom (Synthetic TAndem Repeat-PROmoter display), a technique developed in our laboratory, will hopefully identify most if not all immediate early transcription factors activated in cultured cells by rhythmic blood-borne and temperature-dependent signals. (2) A transgenic mouse model with conditionally active liver clocks will be explored in the genome-wide identification of coding and non-coding transcripts whose rhythmic accumulation is system-driven. The in vivo significance of the components emerging from these approaches will be assessed via RNA interference. Thus, relevant siRNAs will be injected into the tail vein of mice, and their effect on the phase of circadian liver gene expression will be monitored in freely moving mice by using whole body fluorescence imaging. Physiologically important components will serve as entry points for the identification of upstream and downstream constituents in the corresponding signal transduction cascades.
Max ERC Funding
2 360 136 €
Duration
Start date: 2010-04-01, End date: 2015-12-31
Project acronym TREATPD
Project Cell and gene therapy based approaches for treatment of Parkinson's disease: from models to clinics
Researcher (PI) Deniz Kirik
Host Institution (HI) MAX IV Laboratory, Lund University
Country Sweden
Call Details Starting Grant (StG), LS5, ERC-2009-StG
Summary Parkinson s disease is one of the common causes of disability in the aging population, representing a major health problem for the affected individuals and a socioeconomic burden to the society. In the present proposal, the applicant puts forward an ambitious but feasible program to tackle a number of significant issues that remain unsolved in the field. He combines his strong track record in animal models of Parkinson s disease and novel cell and gene therapy-based therapeutic strategies with powerful bio-imaging techniques in order to make bold steps towards translation of new and better treatments to patients suffering from this illness. He does so in a manner that combines, on one hand, the strength of clearly-defined hypotheses and well-established tools for results towards clinical translation, with high-risk high-reward projects that hold the potential to yield ground-breaking discoveries in implementation of novel imaging techniques, on the other.
Summary
Parkinson s disease is one of the common causes of disability in the aging population, representing a major health problem for the affected individuals and a socioeconomic burden to the society. In the present proposal, the applicant puts forward an ambitious but feasible program to tackle a number of significant issues that remain unsolved in the field. He combines his strong track record in animal models of Parkinson s disease and novel cell and gene therapy-based therapeutic strategies with powerful bio-imaging techniques in order to make bold steps towards translation of new and better treatments to patients suffering from this illness. He does so in a manner that combines, on one hand, the strength of clearly-defined hypotheses and well-established tools for results towards clinical translation, with high-risk high-reward projects that hold the potential to yield ground-breaking discoveries in implementation of novel imaging techniques, on the other.
Max ERC Funding
1 508 940 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym TROPGEO
Project Tropical Geometry
Researcher (PI) Grigory Mikhalkin
Host Institution (HI) UNIVERSITE DE GENEVE
Country Switzerland
Call Details Advanced Grant (AdG), PE1, ERC-2009-AdG
Summary The goal of this project is to develop Tropical Geometry, a newly emerging kind of algebraic geometry. It is expected to be more powerful than Classical Geometry in a range of applications (particularly in Physics-minded applications). In the same time it is significantly simpler in several mathematical aspects. In the last decade a number of initial applications of this new geometry has appeared with a success, particularly in the framework of the so-called Gromov-Witten theory, based on curves, i.e. 1-dimensional algebraic varieties. The new subject became known as Tropical Geometry since algebraically it is a based on the so-called ``Tropical Calculus'' of Computer Science. In the tropical world the curves are metric graphs, sometimes enhanced with additional structure. Stepping forward from my recent successes in set-up and application of Tropical Geometry I plan to continue this work. Particularly I plan to advance the following challenging lines of research:
Solve several classical complex enumerative problems, particularly compute ZeuthenÕs characteristic numbers.
Develop tropical homology theories.
Advance the theory of amoebas and coamoebas (algae) of algebraic varieties.
Advance understanding of real algebraic geometry.
Establish direct relation between Feynman diagrams and tropical curves.
Break Òthe Gromov-Witten barrierÓ in Enumerative Geometry.
Develop birational tropical geometry in higher dimensions.
These directions are intrinsically related in their scope and suggested methodology. Some of the proposed goals are very ambitious, but even partial advances would mean a big step forward.
Summary
The goal of this project is to develop Tropical Geometry, a newly emerging kind of algebraic geometry. It is expected to be more powerful than Classical Geometry in a range of applications (particularly in Physics-minded applications). In the same time it is significantly simpler in several mathematical aspects. In the last decade a number of initial applications of this new geometry has appeared with a success, particularly in the framework of the so-called Gromov-Witten theory, based on curves, i.e. 1-dimensional algebraic varieties. The new subject became known as Tropical Geometry since algebraically it is a based on the so-called ``Tropical Calculus'' of Computer Science. In the tropical world the curves are metric graphs, sometimes enhanced with additional structure. Stepping forward from my recent successes in set-up and application of Tropical Geometry I plan to continue this work. Particularly I plan to advance the following challenging lines of research:
Solve several classical complex enumerative problems, particularly compute ZeuthenÕs characteristic numbers.
Develop tropical homology theories.
Advance the theory of amoebas and coamoebas (algae) of algebraic varieties.
Advance understanding of real algebraic geometry.
Establish direct relation between Feynman diagrams and tropical curves.
Break Òthe Gromov-Witten barrierÓ in Enumerative Geometry.
Develop birational tropical geometry in higher dimensions.
These directions are intrinsically related in their scope and suggested methodology. Some of the proposed goals are very ambitious, but even partial advances would mean a big step forward.
Max ERC Funding
1 928 800 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym UFO
Project Uncovering the origins of friction
Researcher (PI) Jean-Francois Molinari
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), PE8, ERC-2009-StG
Summary Nanotechnology is a new frontier in research and new tools must be developed. As surface to volume ratios become large, engineering at the nanoscale will be dominated by surface science. The study of Contact Mechanics at nanoscales nanotribology- needs to fully account for adhesive forces, third-body interactions and deformation mechanisms at contacting asperities. Understanding these factors as well as the morphological evolution of contact clusters has the potential of explaining the origins of frictional forces and wear. This will guide us in the design of tailored-made lubricants and surface morphologies, which, in turn, will help reduce the high societal cost of wear damage. This ERCstg proposal describes a plan to establish a world-leading group in Contact Mechanics at length scales ranging from the atomic to macroscopic scales relevant to Civil or Mechanical Engineering structural applications. Our approach will have recourse to molecular dynamics coupled with the finite-element method for an accurate description of atomic interactions at the contact surface, and of long-range elastic forces. The project is interdisciplinary as the deepening of our understanding of Contact Mechanics will necessitate Computer Science developments. A central objective of the research will be the release of an open, 3D parallel, finite-element platform dedicated to contact applications. The PI will assemble a team of Engineers and Computer Scientists to ensure a successful and perennial diffusion in the European academic and industrial network. The research will therefore explore the origins of friction, a scientific quest of fundamental importance to many industrial applications, and will also create a stable base for sharing scientific-computing resources.
Summary
Nanotechnology is a new frontier in research and new tools must be developed. As surface to volume ratios become large, engineering at the nanoscale will be dominated by surface science. The study of Contact Mechanics at nanoscales nanotribology- needs to fully account for adhesive forces, third-body interactions and deformation mechanisms at contacting asperities. Understanding these factors as well as the morphological evolution of contact clusters has the potential of explaining the origins of frictional forces and wear. This will guide us in the design of tailored-made lubricants and surface morphologies, which, in turn, will help reduce the high societal cost of wear damage. This ERCstg proposal describes a plan to establish a world-leading group in Contact Mechanics at length scales ranging from the atomic to macroscopic scales relevant to Civil or Mechanical Engineering structural applications. Our approach will have recourse to molecular dynamics coupled with the finite-element method for an accurate description of atomic interactions at the contact surface, and of long-range elastic forces. The project is interdisciplinary as the deepening of our understanding of Contact Mechanics will necessitate Computer Science developments. A central objective of the research will be the release of an open, 3D parallel, finite-element platform dedicated to contact applications. The PI will assemble a team of Engineers and Computer Scientists to ensure a successful and perennial diffusion in the European academic and industrial network. The research will therefore explore the origins of friction, a scientific quest of fundamental importance to many industrial applications, and will also create a stable base for sharing scientific-computing resources.
Max ERC Funding
1 773 000 €
Duration
Start date: 2009-09-01, End date: 2014-08-31
Project acronym ULTRANMR
Project Ultrafast Hyperpolarized NMR and MRI in Multiple Dimensions
Researcher (PI) Lucio Frydman
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Advanced Grant (AdG), PE4, ERC-2009-AdG
Summary Multidimensional nuclear magnetic resonance (nD NMR) plays a unique role in Science as a primary tool for the characterization of biomolecules, as part of drug-discovery processes, and in clinical imaging (MRI). Further progress in NMR is hampered by this spectroscopy s low sensitivity, arising from the weak interactions that it involves. The prospects of solving this problem by continuing with incremental bigger machines approaches are poor, given the high maturity reached by existing technologies. The present Project deals with this issue by departing from traditional concepts, and relying on two incipient but highly promising developments in the field. One of these pertains ex situ dynamic nuclear hyperpolarization, an approach capable of eliciting liquid state NMR signals that surpass those afforded by the highest-field spectrometers by factors e10,000. While capable of providing super-signals hyperpolarization has the drawback of involving irreversible changes in the physical state of the sample. This makes it incompatible with nD NMR technologies, requiring the collection of multiple scans identical to one another except for systematic delay variations. As second component in this high-risk/high-gain Project we propose merging hyperpolarization with "ultrafast" methods that we have recently developed for completing arbitrary nD NMR/MRI acquisitions within a single scan. The resulting synergy could increase sensitivity by orders of magnitude, while demanding negligibly small amounts of spectrometer/scanner time to complete nD acquisitions. This should provide an ideal starting point for the analysis of a variety of organic and structural biology problems, and provide new tools to explore in vivo metabolism focusing on cancer biomarkers.
Summary
Multidimensional nuclear magnetic resonance (nD NMR) plays a unique role in Science as a primary tool for the characterization of biomolecules, as part of drug-discovery processes, and in clinical imaging (MRI). Further progress in NMR is hampered by this spectroscopy s low sensitivity, arising from the weak interactions that it involves. The prospects of solving this problem by continuing with incremental bigger machines approaches are poor, given the high maturity reached by existing technologies. The present Project deals with this issue by departing from traditional concepts, and relying on two incipient but highly promising developments in the field. One of these pertains ex situ dynamic nuclear hyperpolarization, an approach capable of eliciting liquid state NMR signals that surpass those afforded by the highest-field spectrometers by factors e10,000. While capable of providing super-signals hyperpolarization has the drawback of involving irreversible changes in the physical state of the sample. This makes it incompatible with nD NMR technologies, requiring the collection of multiple scans identical to one another except for systematic delay variations. As second component in this high-risk/high-gain Project we propose merging hyperpolarization with "ultrafast" methods that we have recently developed for completing arbitrary nD NMR/MRI acquisitions within a single scan. The resulting synergy could increase sensitivity by orders of magnitude, while demanding negligibly small amounts of spectrometer/scanner time to complete nD acquisitions. This should provide an ideal starting point for the analysis of a variety of organic and structural biology problems, and provide new tools to explore in vivo metabolism focusing on cancer biomarkers.
Max ERC Funding
2 499 780 €
Duration
Start date: 2010-03-01, End date: 2015-02-28
Project acronym UMICIS
Project Uncultivated Microbes In Situ - a Computational Biology Approach to Determine Molecular Capabilities and Ecological Roles
Researcher (PI) Christian Von Mering
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Starting Grant (StG), LS2, ERC-2009-StG
Summary Most of nature s biodiversity, and many potentially useful metabolic capabilities, remain hidden among the vast numbers of uncharacterized environmental microbes. Because cultivation is still not possible for most of these microbes, cultivation-independent molecular techniques such as polymerase chain reaction (PCR), fluorescent in situ hybridization (FISH), or shotgun DNA sequencing have been used in order to study their function and ecology in their natural habitats. However, none of the above techniques have so far been sufficient for any systematic assignment of molecular functions to distinct microbial lineages. Thus, most of the molecular ecology of natural microbes remains elusive. Here, we propose a computational meta-analysis and synthesis of existing and newly generated molecular sequence data sampled directly from the environment combining DNA sequencing data (metagenomics), and proteome expression data (metaproteomics). This analysis will be coupled to computational modelling of genome content evolution at the community level. We will aim to assess how gene repertoires of microbial communities, and their taxonomic compositions, change across distinct environments, in response to changed conditions, and through time. We plan to address fundamental questions in microbial ecology, including the extent of cooperation among members of the communities, stability of community composition at evolutionary timescales, the importance of lateral gene transfers, the extent of functional adaptation/regulation in situ, and whether gene occurrence and expression patterns are diagnostic of community functions and ecological status.
Summary
Most of nature s biodiversity, and many potentially useful metabolic capabilities, remain hidden among the vast numbers of uncharacterized environmental microbes. Because cultivation is still not possible for most of these microbes, cultivation-independent molecular techniques such as polymerase chain reaction (PCR), fluorescent in situ hybridization (FISH), or shotgun DNA sequencing have been used in order to study their function and ecology in their natural habitats. However, none of the above techniques have so far been sufficient for any systematic assignment of molecular functions to distinct microbial lineages. Thus, most of the molecular ecology of natural microbes remains elusive. Here, we propose a computational meta-analysis and synthesis of existing and newly generated molecular sequence data sampled directly from the environment combining DNA sequencing data (metagenomics), and proteome expression data (metaproteomics). This analysis will be coupled to computational modelling of genome content evolution at the community level. We will aim to assess how gene repertoires of microbial communities, and their taxonomic compositions, change across distinct environments, in response to changed conditions, and through time. We plan to address fundamental questions in microbial ecology, including the extent of cooperation among members of the communities, stability of community composition at evolutionary timescales, the importance of lateral gene transfers, the extent of functional adaptation/regulation in situ, and whether gene occurrence and expression patterns are diagnostic of community functions and ecological status.
Max ERC Funding
1 129 800 €
Duration
Start date: 2010-02-01, End date: 2016-01-31
Project acronym UPCON
Project Ultra-Pure nanowire heterostructures and energy CONversion
Researcher (PI) Anna Fontcuberta I Morral
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Starting Grant (StG), PE5, ERC-2009-StG
Summary This proposal is devoted to the synthesis of ultra-pure semiconductor nanowire heterostructures for energy conversion applications in the photovoltaic domain. Nanowires are filamentary crystals with a very high ratio of length to diameter, the latter being in the nanometer range. Nanowires are of significant interest owing to their large surface-to-volume ratio and low-dimensional properties, as well as attractive building blocks of novel devices, including for novel energy conversion applications. The most widely employed nanowire growth method relies on the use of gold, which is known to be an impurity limiting mobility and carrier lifetime in semiconductors. It is generally realized that nanowires with higher purity could enable significant advances in both fundamental studies and technological applications. This proposal combines two complementary and essential aspects of semiconductor nanowires: (i) synthesis in extremely clean conditions and (ii) their application to new concepts of photovoltaic devices. The first part involves the use of Molecular Beam Epitaxy (MBE) system for the synthesis of III-V semiconductor nanowires and heterostructures. Special emphasis will be given in the synthesis of new heterostructure designs, i.e. across the nanowire radius and along the growth axis. The fabrication of ordered arrays of nanowires on large areas and on silicon substrates will also be investigated. In the second part, nanowire based solar cells will be designed, fabricated and characterized. Particular emphasis will be given toward understanding the role of geometry and interfaces in the energy conversion efficiency of the novel nanowire-based solar cells. Here, the high cleanliness and precise heteroepitaxial growth of MBE nanowires will allow us to perform fundamental studies, generating ground-breaking knowledge on the microscopic processes in energy conversion. This project will foster the use of nanotechnology in the energy challenges of the XXI century.
Summary
This proposal is devoted to the synthesis of ultra-pure semiconductor nanowire heterostructures for energy conversion applications in the photovoltaic domain. Nanowires are filamentary crystals with a very high ratio of length to diameter, the latter being in the nanometer range. Nanowires are of significant interest owing to their large surface-to-volume ratio and low-dimensional properties, as well as attractive building blocks of novel devices, including for novel energy conversion applications. The most widely employed nanowire growth method relies on the use of gold, which is known to be an impurity limiting mobility and carrier lifetime in semiconductors. It is generally realized that nanowires with higher purity could enable significant advances in both fundamental studies and technological applications. This proposal combines two complementary and essential aspects of semiconductor nanowires: (i) synthesis in extremely clean conditions and (ii) their application to new concepts of photovoltaic devices. The first part involves the use of Molecular Beam Epitaxy (MBE) system for the synthesis of III-V semiconductor nanowires and heterostructures. Special emphasis will be given in the synthesis of new heterostructure designs, i.e. across the nanowire radius and along the growth axis. The fabrication of ordered arrays of nanowires on large areas and on silicon substrates will also be investigated. In the second part, nanowire based solar cells will be designed, fabricated and characterized. Particular emphasis will be given toward understanding the role of geometry and interfaces in the energy conversion efficiency of the novel nanowire-based solar cells. Here, the high cleanliness and precise heteroepitaxial growth of MBE nanowires will allow us to perform fundamental studies, generating ground-breaking knowledge on the microscopic processes in energy conversion. This project will foster the use of nanotechnology in the energy challenges of the XXI century.
Max ERC Funding
1 286 000 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym WORDS
Project Words and Waring type problems
Researcher (PI) Aner Shalev
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Advanced Grant (AdG), PE1, ERC-2009-AdG
Summary Hilbert's solution to Waring problem in Number Theory shows that every positive integer is a sum of g(n) nth powers. Surprising non-commutative analogues of this phenomenon were discovered recently in Group Theory, where powers are replaced by general words. Moreover, the study of group words occurs naturally in important contexts, such as the Burnside problems, Serre's problem on profinite groups, and finite simple group theory. We propose a systematic study of word maps on groups, their images and kernels, as well as related Waring type problems. These include a celebrated conjecture of Thompson, problems regarding covering numbers and mixing times of random walks, as well as probabilistic identities in finite and profinite groups. This is a highly challenging project in which we intend to utilize a wide spectrum of tools, including Representation Theory, Algebraic Geometry, Number Theory, computational group theory, as well as probabilistic methods and Lie methods. Moreover, we aim to establish new results on representations and character bounds, which would be very useful in various additional contexts. Apart from their intrinsic interest, the problems and conjectures we propose have exciting applications to other fields, and the project is likely to shed new light not just in group theory but also in combinatorics, probability and geometry.
Summary
Hilbert's solution to Waring problem in Number Theory shows that every positive integer is a sum of g(n) nth powers. Surprising non-commutative analogues of this phenomenon were discovered recently in Group Theory, where powers are replaced by general words. Moreover, the study of group words occurs naturally in important contexts, such as the Burnside problems, Serre's problem on profinite groups, and finite simple group theory. We propose a systematic study of word maps on groups, their images and kernels, as well as related Waring type problems. These include a celebrated conjecture of Thompson, problems regarding covering numbers and mixing times of random walks, as well as probabilistic identities in finite and profinite groups. This is a highly challenging project in which we intend to utilize a wide spectrum of tools, including Representation Theory, Algebraic Geometry, Number Theory, computational group theory, as well as probabilistic methods and Lie methods. Moreover, we aim to establish new results on representations and character bounds, which would be very useful in various additional contexts. Apart from their intrinsic interest, the problems and conjectures we propose have exciting applications to other fields, and the project is likely to shed new light not just in group theory but also in combinatorics, probability and geometry.
Max ERC Funding
1 197 800 €
Duration
Start date: 2010-01-01, End date: 2014-12-31