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 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 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 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