Project acronym ADIPODIF
Project Adipocyte Differentiation and Metabolic Functions in Obesity and Type 2 Diabetes
Researcher (PI) Christian Wolfrum
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Country Switzerland
Call Details Starting Grant (StG), LS6, ERC-2007-StG
Summary Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.
Summary
Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.
Max ERC Funding
1 607 105 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym CENDUP
Project Decoding the mechanisms of centrosome duplication
Researcher (PI) Pierre Goenczy
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), LS3, ERC-2008-AdG
Summary Centrosome duplication entails the formation of a single procentriole next to each centriole once per cell cycle. The mechanisms governing procentriole formation are poorly understood and constitute a fundamental open question in cell biology. We will launch an innovative multidisciplinary research program to gain significant insight into these mechanisms using C. elegans and human cells. This research program is also expected to have a significant impact by contributing important novel assays to the field. Six specific aims will be pursued: 1) SAS-6 as a ZYG-1 substrate: mechanisms of procentriole formation in C. elegans. We will test in vivo the consequence of SAS-6 phosphorylation by ZYG-1. 2) Biochemical and structural analysis of SAS-6-containing macromolecular complexes (SAMACs). We will isolate and characterize SAMACs from C. elegans embryos and human cells, and analyze their structure using single-particle electron microscopy. 3) Novel cell-free assay for procentriole formation in human cells. We will develop such an assay and use it to test whether SAMACs can direct procentriole formation and whether candidate proteins are needed at centrioles or in the cytoplasm. 4) Mapping interactions between centriolar proteins in live human cells. We will use chemical methods developed by our collaborators to probe interactions between HsSAS-6 and centriolar proteins in a time- and space-resolved manner. 5) Functional genomic and chemical genetic screens in human cells. We will conduct high-throughput fluorescence-based screens in human cells to identify novel genes required for procentriole formation and small molecule inhibitors of this process. 6) Mechanisms underlying differential centriolar maintenance in the germline. In C. elegans, we will characterize how the sas-1 locus is required for centriole maintenance during spermatogenesis, as well as analyze centriole elimination during oogenesis and identify components needed for this process
Summary
Centrosome duplication entails the formation of a single procentriole next to each centriole once per cell cycle. The mechanisms governing procentriole formation are poorly understood and constitute a fundamental open question in cell biology. We will launch an innovative multidisciplinary research program to gain significant insight into these mechanisms using C. elegans and human cells. This research program is also expected to have a significant impact by contributing important novel assays to the field. Six specific aims will be pursued: 1) SAS-6 as a ZYG-1 substrate: mechanisms of procentriole formation in C. elegans. We will test in vivo the consequence of SAS-6 phosphorylation by ZYG-1. 2) Biochemical and structural analysis of SAS-6-containing macromolecular complexes (SAMACs). We will isolate and characterize SAMACs from C. elegans embryos and human cells, and analyze their structure using single-particle electron microscopy. 3) Novel cell-free assay for procentriole formation in human cells. We will develop such an assay and use it to test whether SAMACs can direct procentriole formation and whether candidate proteins are needed at centrioles or in the cytoplasm. 4) Mapping interactions between centriolar proteins in live human cells. We will use chemical methods developed by our collaborators to probe interactions between HsSAS-6 and centriolar proteins in a time- and space-resolved manner. 5) Functional genomic and chemical genetic screens in human cells. We will conduct high-throughput fluorescence-based screens in human cells to identify novel genes required for procentriole formation and small molecule inhibitors of this process. 6) Mechanisms underlying differential centriolar maintenance in the germline. In C. elegans, we will characterize how the sas-1 locus is required for centriole maintenance during spermatogenesis, as well as analyze centriole elimination during oogenesis and identify components needed for this process
Max ERC Funding
2 004 155 €
Duration
Start date: 2009-04-01, End date: 2014-03-31
Project acronym COSPSENA
Project Coherence of Spins in Semiconductor Nanostructures
Researcher (PI) Dominik Max Zumbuehl
Host Institution (HI) UNIVERSITAT BASEL
Country Switzerland
Call Details Starting Grant (StG), PE3, ERC-2007-StG
Summary Macroscopic control of quantum states is a major theme in much of modern physics because quantum coherence enables study of fundamental physics and has promising applications for quantum information processing. The potential significance of quantum computing is recognized well beyond the physics community. For electron spins in GaAs quantum dots, it has become clear that decoherence caused by interactions with the nuclear spins is a major challenge. We propose to investigate and reduce hyperfine induced decoherence with two complementary approaches: nuclear spin state narrowing and nuclear spin polarization. We propose a new projective state narrowing technique: a large, Coulomb blockaded dot measures the qubit nuclear ensemble, resulting in enhanced spin coherence times. Further, mediated by an interacting 2D electron gas via hyperfine interaction, a low temperature nuclear ferromagnetic spin state was predicted, which we propose to investigate using a quantum point contact as a nuclear polarization detector. Estimates indicate that the nuclear ferromagnetic transition occurs in the sub-Millikelvin range, well below already hard to reach temperatures around 10 mK. However, the exciting combination of interacting electron and nuclear spin physics as well as applications in spin qubits give ample incentive to strive for sub-Millikelvin temperatures in nanostructures. We propose to build a novel type of nuclear demagnetization refrigerator aiming to reach electron temperatures of 0.1 mK in semiconductor nanostructures. This interdisciplinary project combines Microkelvin and nanophysics, going well beyond the status quo. It is a challenging project that could be the beginning of a new era of coherent spin physics with unprecedented quantum control. This project requires a several year commitment and a team of two graduate students plus one postdoctoral fellow.
Summary
Macroscopic control of quantum states is a major theme in much of modern physics because quantum coherence enables study of fundamental physics and has promising applications for quantum information processing. The potential significance of quantum computing is recognized well beyond the physics community. For electron spins in GaAs quantum dots, it has become clear that decoherence caused by interactions with the nuclear spins is a major challenge. We propose to investigate and reduce hyperfine induced decoherence with two complementary approaches: nuclear spin state narrowing and nuclear spin polarization. We propose a new projective state narrowing technique: a large, Coulomb blockaded dot measures the qubit nuclear ensemble, resulting in enhanced spin coherence times. Further, mediated by an interacting 2D electron gas via hyperfine interaction, a low temperature nuclear ferromagnetic spin state was predicted, which we propose to investigate using a quantum point contact as a nuclear polarization detector. Estimates indicate that the nuclear ferromagnetic transition occurs in the sub-Millikelvin range, well below already hard to reach temperatures around 10 mK. However, the exciting combination of interacting electron and nuclear spin physics as well as applications in spin qubits give ample incentive to strive for sub-Millikelvin temperatures in nanostructures. We propose to build a novel type of nuclear demagnetization refrigerator aiming to reach electron temperatures of 0.1 mK in semiconductor nanostructures. This interdisciplinary project combines Microkelvin and nanophysics, going well beyond the status quo. It is a challenging project that could be the beginning of a new era of coherent spin physics with unprecedented quantum control. This project requires a several year commitment and a team of two graduate students plus one postdoctoral fellow.
Max ERC Funding
1 377 000 €
Duration
Start date: 2008-06-01, End date: 2013-05-31
Project acronym DROSOPHILASIGNALING
Project Signaling Pathways Controlling Patterning, Growth and Final Size of Drosophila Limbs
Researcher (PI) Konrad Basler
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Advanced Grant (AdG), LS3, ERC-2008-AdG
Summary Developmental biology seeks not only to learn more about the fundamental processes of growth and pattern per se, but to understand how they synergize to enable the morphogenesis of multicellular organisms. Our goal is to perform real-time analyses of these developmental processes in an intact developing organ. By applying a vital imaging approach, we can circumvent the normal limitations of inferring cellular dynamics from static images or molecular data, and obtain the real dynamic view of growth and patterning. The wing imaginal disc of Drosophila, which starts out as a simple epithelial structure and gives rise to a precisely structured adult limb, will serve as an ideal model system. This system has the combined advantages of relative simplicity and genetic tractability. We will create several innovations that expand the current toolkit and thus facilitate the detailed dissection of growth and patterning. A key early step will be to develop novel reporters to dynamically and faithfully monitor signaling cascades involved in growth and patterning, such as the Dpp and Hippo pathways. We will also implement quantification techniques that are currently being set up in collaboration with an experimental physicist, to deduce, and alter, the mechanical forces that develop in the cells of a growing tissue. The large amount of quantitative data that will be generated allow us derive computational models of the individual pathways and their interaction. The focus of the study will be to answer the following questions: 1) Is the Hippo pathway regulated spatially and temporally, and by what signaling pathways? 2) Do mechanical forces play a pivotal controlling role in organ morphogenesis? 3) What are the global effects on growth, when pathways controlling patterning, cell competition or compensatory proliferation are perturbed? The proposed project will bring the approaches taken to define the mechanisms underlying and controlling growth and patterning to the next level.
Summary
Developmental biology seeks not only to learn more about the fundamental processes of growth and pattern per se, but to understand how they synergize to enable the morphogenesis of multicellular organisms. Our goal is to perform real-time analyses of these developmental processes in an intact developing organ. By applying a vital imaging approach, we can circumvent the normal limitations of inferring cellular dynamics from static images or molecular data, and obtain the real dynamic view of growth and patterning. The wing imaginal disc of Drosophila, which starts out as a simple epithelial structure and gives rise to a precisely structured adult limb, will serve as an ideal model system. This system has the combined advantages of relative simplicity and genetic tractability. We will create several innovations that expand the current toolkit and thus facilitate the detailed dissection of growth and patterning. A key early step will be to develop novel reporters to dynamically and faithfully monitor signaling cascades involved in growth and patterning, such as the Dpp and Hippo pathways. We will also implement quantification techniques that are currently being set up in collaboration with an experimental physicist, to deduce, and alter, the mechanical forces that develop in the cells of a growing tissue. The large amount of quantitative data that will be generated allow us derive computational models of the individual pathways and their interaction. The focus of the study will be to answer the following questions: 1) Is the Hippo pathway regulated spatially and temporally, and by what signaling pathways? 2) Do mechanical forces play a pivotal controlling role in organ morphogenesis? 3) What are the global effects on growth, when pathways controlling patterning, cell competition or compensatory proliferation are perturbed? The proposed project will bring the approaches taken to define the mechanisms underlying and controlling growth and patterning to the next level.
Max ERC Funding
2 310 000 €
Duration
Start date: 2009-02-01, End date: 2014-01-31
Project acronym DSBREPAIR
Project Developmental and Genetic Analysis of DNA Double-Strand Break Repair
Researcher (PI) Marcel Tijsterman
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Country Netherlands
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary The DNA within our cells is constantly being damaged by both environmental and endogenous agents; of the many forms of DNA damage, the DNA double-strand break (DSB) is considered to be most dangerous. Correct processing of DSBs is not only essential for maintaining genomic integrity but is also required in specific biological processes, such as meiotic recombination and V(D)J recombination, in which DNA breaks are deliberately generated. In animals, defects in the proper response to DSBs can thus have different outcomes: cancer predisposition, embryonic lethality, or compromised immunity. Many genes that play a role in the processing of DSBs have been identified over the past decades, mainly by cloning genes that are responsible for specific human genomic instability or immune deficiency syndromes, and by genetic approaches using unicellular eukaryotes and rodent cell lines. It is, however, evident that many components required in higher eukaryotes are not yet known and the identification of those will be a major challenge for future research. Here, we will for the first time systematically test all genes encoded by an animals genome directly for their involvement in the cellular response to DSB in both somatic and germline tissues: we will use our recently developed transgenic animal models (C. elegans) that visualizes repair of a single localized genomic DNA break in genome wide RNAi screenings to identify (and then characterize) the complement of genes that are required to keep our genome stable, and when mutated can predispose humans to cancer. In parallel, we will study the cellular response to single DNA breaks that are artificially generated during different stages of gametogenesis, as well as address the developmental consequences of DSB induction during the earliest stages of embryonic development – an almost completely unexplored area in the field of genome instability and DNA damage responses.
Summary
The DNA within our cells is constantly being damaged by both environmental and endogenous agents; of the many forms of DNA damage, the DNA double-strand break (DSB) is considered to be most dangerous. Correct processing of DSBs is not only essential for maintaining genomic integrity but is also required in specific biological processes, such as meiotic recombination and V(D)J recombination, in which DNA breaks are deliberately generated. In animals, defects in the proper response to DSBs can thus have different outcomes: cancer predisposition, embryonic lethality, or compromised immunity. Many genes that play a role in the processing of DSBs have been identified over the past decades, mainly by cloning genes that are responsible for specific human genomic instability or immune deficiency syndromes, and by genetic approaches using unicellular eukaryotes and rodent cell lines. It is, however, evident that many components required in higher eukaryotes are not yet known and the identification of those will be a major challenge for future research. Here, we will for the first time systematically test all genes encoded by an animals genome directly for their involvement in the cellular response to DSB in both somatic and germline tissues: we will use our recently developed transgenic animal models (C. elegans) that visualizes repair of a single localized genomic DNA break in genome wide RNAi screenings to identify (and then characterize) the complement of genes that are required to keep our genome stable, and when mutated can predispose humans to cancer. In parallel, we will study the cellular response to single DNA breaks that are artificially generated during different stages of gametogenesis, as well as address the developmental consequences of DSB induction during the earliest stages of embryonic development – an almost completely unexplored area in the field of genome instability and DNA damage responses.
Max ERC Funding
1 060 000 €
Duration
Start date: 2008-05-01, End date: 2014-04-30
Project acronym EQUIARITH
Project Equidistribution in number theory
Researcher (PI) Philippe Michel
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), PE1, ERC-2008-AdG
Summary The purpose of this proposal is to investigate from various perspectives some equidistribution problems associated with homogeneous spaces of arithmetic type: a typical problem (basically solved) is the distribution of the set of representations of a large integer by an integral quadratic form. Another harder problem is the study of the distribution of special points on Shimura varieties. In a different direction (linked with quantum chaos), the study of the concentration of Laplacian (Maass) eigenforms or of sections of holomorphic bundles is related to similar problems. Given X such a space and G>L the underlying algebraic group and its corresponding lattice L, the above questions boil down to studying the distribution of H-orbits x.H (or more generally H-invariant measures)on the quotient L\G for some subgroups H. This question may be studied different methods: Harmonic Analysis (HA): given a function f on L\G one studies the period integral of f along x.H. This may be done by automorphic methods. In favorable circumstances, the above periods are related to L-functions which one may hope to treat by methods from analytic number theory (the subconvexity problem). Ergodic Theory (ET): one studies the properties of weak*-limits of the measures supported by x.H using rigidity techniques: depending on the nature of H, one might use either rigidity of unipotent actions or the more recent rigidity results for torus actions in rank >1. In fact, HA and ET are intertwined and complementary : the use of ET in this context require a substantial input from number theory and HA, while ET lead to a soft understanding of several features of HA. In addition, the Langlands correspondence principle make it possible to pass from one group G to another. Based on earlier experience, our goal is to develop these interactions systematically and to develop new approaches to outstanding arithmetic problems :eg. the subconvexity problem or the Andre/Oort conjecture.
Summary
The purpose of this proposal is to investigate from various perspectives some equidistribution problems associated with homogeneous spaces of arithmetic type: a typical problem (basically solved) is the distribution of the set of representations of a large integer by an integral quadratic form. Another harder problem is the study of the distribution of special points on Shimura varieties. In a different direction (linked with quantum chaos), the study of the concentration of Laplacian (Maass) eigenforms or of sections of holomorphic bundles is related to similar problems. Given X such a space and G>L the underlying algebraic group and its corresponding lattice L, the above questions boil down to studying the distribution of H-orbits x.H (or more generally H-invariant measures)on the quotient L\G for some subgroups H. This question may be studied different methods: Harmonic Analysis (HA): given a function f on L\G one studies the period integral of f along x.H. This may be done by automorphic methods. In favorable circumstances, the above periods are related to L-functions which one may hope to treat by methods from analytic number theory (the subconvexity problem). Ergodic Theory (ET): one studies the properties of weak*-limits of the measures supported by x.H using rigidity techniques: depending on the nature of H, one might use either rigidity of unipotent actions or the more recent rigidity results for torus actions in rank >1. In fact, HA and ET are intertwined and complementary : the use of ET in this context require a substantial input from number theory and HA, while ET lead to a soft understanding of several features of HA. In addition, the Langlands correspondence principle make it possible to pass from one group G to another. Based on earlier experience, our goal is to develop these interactions systematically and to develop new approaches to outstanding arithmetic problems :eg. the subconvexity problem or the Andre/Oort conjecture.
Max ERC Funding
866 000 €
Duration
Start date: 2008-12-01, End date: 2013-11-30
Project acronym HIGHZ
Project HIGHZ: Elucidating galaxy formation and evolution from very deep Near-IR imaging
Researcher (PI) Marijn Franx
Host Institution (HI) UNIVERSITEIT LEIDEN
Country Netherlands
Call Details Advanced Grant (AdG), PE9, ERC-2008-AdG
Summary "Studies of high redshift galaxies require very deep Near-IR imaging. This allows the study of z=2-4 galaxies redward of the Balmer/4000 Angstrom break, and the detection of UV-bright galaxies at z>7. Two new facilities wil revolutionize these studies: the VISTA telescope built for ESO, and the Near-IR channel on WF3 for HST. They will become available at the start of the grant period. We propose to build a group to analyze the imaging data from these facilities. We will make use of the fact that I am Co-PI on the ultra-deep ""ULTRA-VISTA"" survey on the VISTA telescope, and we will analyze public and privately proposed data from WF3. The following science questions will be addressed: (1) what is the origin and evolution of the Hubble sequence out to z=3, (2) what is the evolution of the Luminosity Function of UV bright galaxies between z=6 to z=11, and what galaxies cause re-ionization, (3) how does the mass function of quiescent and star forming galaxies evolve to z=4, and how do the correlation functions of subpopulations evolve as a function of redshift. A crucial component of this proposal is the request for support for a junior faculty position. This person will take on the lead for the highly specialized data processing, and will supervise the analysis of the selection effects, and other crucial components needed for a proper analysis."
Summary
"Studies of high redshift galaxies require very deep Near-IR imaging. This allows the study of z=2-4 galaxies redward of the Balmer/4000 Angstrom break, and the detection of UV-bright galaxies at z>7. Two new facilities wil revolutionize these studies: the VISTA telescope built for ESO, and the Near-IR channel on WF3 for HST. They will become available at the start of the grant period. We propose to build a group to analyze the imaging data from these facilities. We will make use of the fact that I am Co-PI on the ultra-deep ""ULTRA-VISTA"" survey on the VISTA telescope, and we will analyze public and privately proposed data from WF3. The following science questions will be addressed: (1) what is the origin and evolution of the Hubble sequence out to z=3, (2) what is the evolution of the Luminosity Function of UV bright galaxies between z=6 to z=11, and what galaxies cause re-ionization, (3) how does the mass function of quiescent and star forming galaxies evolve to z=4, and how do the correlation functions of subpopulations evolve as a function of redshift. A crucial component of this proposal is the request for support for a junior faculty position. This person will take on the lead for the highly specialized data processing, and will supervise the analysis of the selection effects, and other crucial components needed for a proper analysis."
Max ERC Funding
1 471 200 €
Duration
Start date: 2009-09-01, End date: 2014-08-31
Project acronym MATHCARD
Project Mathematical Modelling and Simulation of the Cardiovascular System
Researcher (PI) Alfio Quarteroni
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), PE1, ERC-2008-AdG
Summary This research project aims at the development, analysis and computer implementation of mathematical models of the cardiovascular system. Our goal is to describe and simulate the anatomic structure and the physiological response of the human cardiovascular system in healthy or diseased states. This demands to address many fundamental issues. Blood flow interacts both mechanically and chemically with the vessel walls and tissue, giving rise to complex fluid-structure interaction problems. The mathematical analysis of these problems is complicated and the related numerical analysis difficult. We propose to extend the recently achieved results on blood flow simulations by directing our analysis in several new directions. Our goal is to encompass aspects of metabolic regulation, micro-circulation, the electrical and mechanical activity of the heart, and their interactions. Modelling and optimisation of drugs delivery in clinical diseases will be addressed as well. This requires the understanding of transport, diffusion and reaction processes within the blood and organs of the body. The emphasis of this project will be put on mathematical modelling, numerical analysis, algorithm implementation, computational efficiency, validation and verification. Our purpose is to set up a mathematical simulation platform eventually leading to the improvement of vascular diseases diagnosis, setting up of surgical planning, and cure of inflammatory processes in the circulatory system. This platform might also help physicians to construct and evaluate combined anatomic/physiological models to predict the outcome of alternative treatment plans for individual patients.
Summary
This research project aims at the development, analysis and computer implementation of mathematical models of the cardiovascular system. Our goal is to describe and simulate the anatomic structure and the physiological response of the human cardiovascular system in healthy or diseased states. This demands to address many fundamental issues. Blood flow interacts both mechanically and chemically with the vessel walls and tissue, giving rise to complex fluid-structure interaction problems. The mathematical analysis of these problems is complicated and the related numerical analysis difficult. We propose to extend the recently achieved results on blood flow simulations by directing our analysis in several new directions. Our goal is to encompass aspects of metabolic regulation, micro-circulation, the electrical and mechanical activity of the heart, and their interactions. Modelling and optimisation of drugs delivery in clinical diseases will be addressed as well. This requires the understanding of transport, diffusion and reaction processes within the blood and organs of the body. The emphasis of this project will be put on mathematical modelling, numerical analysis, algorithm implementation, computational efficiency, validation and verification. Our purpose is to set up a mathematical simulation platform eventually leading to the improvement of vascular diseases diagnosis, setting up of surgical planning, and cure of inflammatory processes in the circulatory system. This platform might also help physicians to construct and evaluate combined anatomic/physiological models to predict the outcome of alternative treatment plans for individual patients.
Max ERC Funding
1 810 992 €
Duration
Start date: 2009-01-01, End date: 2014-06-30
Project acronym MMPF
Project Molecular Movies of Protein Folding
Researcher (PI) Sander Woutersen
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Country Netherlands
Call Details Starting Grant (StG), PE3, ERC-2007-StG
Summary Protein folding, the process by which a protein assumes its three-dimensional shape, is one of the basic unsolved problems of biophysical and biochemical research. Many of the structural changes taking place during protein folding, especially during the early stages, are as yet poorly understood. This is because high-resolution structural techniques generally lack the time resolution necessary for observation of folding dynamics, whereas methods that have the required time resolution generally lack structural specificity. We propose an experimental approach that combines the structure-sensitivity of multi-dimensional NMR with the ultrafast time resolution of optical techniques. To do this, we use two-dimensional optical spectroscopy (in particular, two-dimensional optical spectroscopy and time-resolved vibrational circular dichroism) in combination with site-specific labeling of proteins. This will make it possible to obtain a structurally and temporally resolved picture of protein folding, which can be regarded as a 'molecular movie' of the folding process. With the proposed method, we will investigate structural changes during protein folding at increasing levels of complexity: from the dynamics of alpha-helix nucleation, to the formation and structural characteristics of intermediate states in small globular proteins and complex beta-sheet topologies, to the nature of biologically functional, short-lived unfolded states in signalling proteins. At each of these levels of complexity, the proposed method will be used to unravel the mechanisms behind the respective folding events.
Summary
Protein folding, the process by which a protein assumes its three-dimensional shape, is one of the basic unsolved problems of biophysical and biochemical research. Many of the structural changes taking place during protein folding, especially during the early stages, are as yet poorly understood. This is because high-resolution structural techniques generally lack the time resolution necessary for observation of folding dynamics, whereas methods that have the required time resolution generally lack structural specificity. We propose an experimental approach that combines the structure-sensitivity of multi-dimensional NMR with the ultrafast time resolution of optical techniques. To do this, we use two-dimensional optical spectroscopy (in particular, two-dimensional optical spectroscopy and time-resolved vibrational circular dichroism) in combination with site-specific labeling of proteins. This will make it possible to obtain a structurally and temporally resolved picture of protein folding, which can be regarded as a 'molecular movie' of the folding process. With the proposed method, we will investigate structural changes during protein folding at increasing levels of complexity: from the dynamics of alpha-helix nucleation, to the formation and structural characteristics of intermediate states in small globular proteins and complex beta-sheet topologies, to the nature of biologically functional, short-lived unfolded states in signalling proteins. At each of these levels of complexity, the proposed method will be used to unravel the mechanisms behind the respective folding events.
Max ERC Funding
1 716 321 €
Duration
Start date: 2008-09-01, End date: 2014-08-31
Project acronym NANOIMMUNE
Project Nanoparticle Vaccines: At the interface of bionanotechnology and adaptive immunity
Researcher (PI) Jeffrey Hubbell
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Country Switzerland
Call Details Advanced Grant (AdG), LS6, ERC-2008-AdG
Summary We have recently developed a bionanotechnology approach to vaccination (Reddy et al., Nature Biotechnology, 25, 1159-1164, 2007): degradable polymeric nanoparticles are designed that: (i) are so small that they can enter the lymphatic circulation by biophysical means; (ii) are efficiently taken up by a large fraction of dendritic cells (DCs) that are resident in the lymph node that drains the injection site; (iii) activate the complement cascade and provide a potent, yet safe, activation signal to those DCs; and (iv) thereby induce a potent, Th1 adaptive immune response to antigen bound to the nanoparticles, with the generation of both antibodies and cytotoxic T lymphocytes. In the present project, we focus on next-generation bionanotechnology vaccine platforms for vaccination. We propose three technological advances, and we propose to demonstrate those three advances in definitive models in the mouse. Specifically, we propose to (Specific Aim 1) evaluate the current approach of complement-mediated DC activation in breaking tolerance to a chronic viral infection (hepatitis B virus, HBV, targeting hepatitis B virus surface antigen, HBsAg) and to combine complement as a danger signal with other nanoparticle-borne danger signals to develop an effective bionanotechnological platform for therapeutic antiviral vaccination; (Specific Aim 2) to develop a new, ultrasmall nanoparticle implementation suitable for delivery of DNA to lymph node-resident DCs, also activating them, to enable more efficient DNA vaccination; and (Specific Aim 3) to develop an ultrasmall nanoparticle implementation suitable for delivery of DNA to DCs resident within the sublingual mucosa, also activating them, to enable efficient DNA mucosal vaccination. The Specific Aim addressing the oral mucosa will begin with HBsAg, to allow comparison to other routes of administration, and will then proceed to antigens from influenza A.
Summary
We have recently developed a bionanotechnology approach to vaccination (Reddy et al., Nature Biotechnology, 25, 1159-1164, 2007): degradable polymeric nanoparticles are designed that: (i) are so small that they can enter the lymphatic circulation by biophysical means; (ii) are efficiently taken up by a large fraction of dendritic cells (DCs) that are resident in the lymph node that drains the injection site; (iii) activate the complement cascade and provide a potent, yet safe, activation signal to those DCs; and (iv) thereby induce a potent, Th1 adaptive immune response to antigen bound to the nanoparticles, with the generation of both antibodies and cytotoxic T lymphocytes. In the present project, we focus on next-generation bionanotechnology vaccine platforms for vaccination. We propose three technological advances, and we propose to demonstrate those three advances in definitive models in the mouse. Specifically, we propose to (Specific Aim 1) evaluate the current approach of complement-mediated DC activation in breaking tolerance to a chronic viral infection (hepatitis B virus, HBV, targeting hepatitis B virus surface antigen, HBsAg) and to combine complement as a danger signal with other nanoparticle-borne danger signals to develop an effective bionanotechnological platform for therapeutic antiviral vaccination; (Specific Aim 2) to develop a new, ultrasmall nanoparticle implementation suitable for delivery of DNA to lymph node-resident DCs, also activating them, to enable more efficient DNA vaccination; and (Specific Aim 3) to develop an ultrasmall nanoparticle implementation suitable for delivery of DNA to DCs resident within the sublingual mucosa, also activating them, to enable efficient DNA mucosal vaccination. The Specific Aim addressing the oral mucosa will begin with HBsAg, to allow comparison to other routes of administration, and will then proceed to antigens from influenza A.
Max ERC Funding
2 499 425 €
Duration
Start date: 2009-05-01, End date: 2014-04-30
