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
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 Forssén
Host Institution (HI) CHALMERS TEKNISKA HOEGSKOLA AB
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 ASD
Project Atomistic Spin-Dynamics; Methodology and Applications
Researcher (PI) Olof Ragnar Eriksson
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Advanced Grant (AdG), PE3, ERC-2009-AdG
Summary Our aim is to provide a theoretical framework for studies of dynamical aspects of magnetic materials and magnetisation reversal, which has potential for applications for magnetic data storage and magnetic memory devices. The project focuses on developing and using an atomistic spin dynamics simulation method. Our goal is to identify novel materials and device geometries with improved performance. The scientific questions which will be addressed concern the understanding of the fundamental temporal limit of magnetisation switching and reversal, and the mechanisms which govern this limit. The methodological developments concern the ability to, from first principles theory, calculate the interatomic exchange parameters of materials in general, in particular for correlated electron materials, via the use of dynamical mean-field theory. The theoretical development also involves an atomistic spin dynamics simulation method, which once it has been established, will be released as a public software package. The proposed theoretical research will be intimately connected to world-leading experimental efforts, especially in Europe where a leading activity in experimental studies of magnetisation dynamics has been established. The ambition with this project is to become world-leading in the theory of simulating spin-dynamics phenomena, and to promote education and training of young researchers. To achieve our goals we will build up an open and lively environment, where the advances in the theoretical knowledge of spin-dynamics phenomena will be used to address important questions in information technology. In this environment the next generation research leaders will be fostered and trained, thus ensuring that the society of tomorrow is equipped with the scientific competence to tackle the challenges of our future.
Summary
Our aim is to provide a theoretical framework for studies of dynamical aspects of magnetic materials and magnetisation reversal, which has potential for applications for magnetic data storage and magnetic memory devices. The project focuses on developing and using an atomistic spin dynamics simulation method. Our goal is to identify novel materials and device geometries with improved performance. The scientific questions which will be addressed concern the understanding of the fundamental temporal limit of magnetisation switching and reversal, and the mechanisms which govern this limit. The methodological developments concern the ability to, from first principles theory, calculate the interatomic exchange parameters of materials in general, in particular for correlated electron materials, via the use of dynamical mean-field theory. The theoretical development also involves an atomistic spin dynamics simulation method, which once it has been established, will be released as a public software package. The proposed theoretical research will be intimately connected to world-leading experimental efforts, especially in Europe where a leading activity in experimental studies of magnetisation dynamics has been established. The ambition with this project is to become world-leading in the theory of simulating spin-dynamics phenomena, and to promote education and training of young researchers. To achieve our goals we will build up an open and lively environment, where the advances in the theoretical knowledge of spin-dynamics phenomena will be used to address important questions in information technology. In this environment the next generation research leaders will be fostered and trained, thus ensuring that the society of tomorrow is equipped with the scientific competence to tackle the challenges of our future.
Max ERC Funding
2 130 000 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym DALDECS
Project Development and Application of Laser Diagnostic Techniques for Combustion Studies
Researcher (PI) Lars Eric Marcus Aldén
Host Institution (HI) LUNDS UNIVERSITET
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 DIADRUG
Project Insulin resistance and diabetic nephropathy - development of novel in vivo models for drug discovery
Researcher (PI) Sanna Lehtonen
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS9, ERC-2009-StG
Summary Up to one third of diabetic patients develop nephropathy, a serious complication of diabetes. Microalbuminuria is the earliest sign of the complication, which may ultimately develop to end-stage renal disease requiring dialysis or a kidney transplant. Insulin resistance and metabolic syndrome are associated with an increased risk for diabetic nephropathy. Interestingly, glomerular epithelial cells or podocytes have recently been shown to be insulin responsive. Further, nephrin, a key structural component of podocytes, is essential for insulin action in these cells. Our novel findings show that adaptor protein CD2AP, an interaction partner of nephrin, associates with regulators of insulin signaling and glucose transport in glomeruli. The results suggest that nephrin and CD2AP are involved, by association with these proteins, in the regulation of insulin signaling and glucose transport in podocytes. We hypothesize that podocytes can develop insulin resistance and that disturbances in insulin response affect podocyte function and contribute to the development of diabetic nephropathy. The aim of this project is to clarify the mechanisms leading to development of insulin resistance in podocytes and to study the association between insulin resistance and the development of diabetic nephropathy. For this we will develop transgenic zebrafish and mouse models by overexpressing/knocking down insulin signaling-associated proteins specifically in podocytes. Further, we aim to identify novel drug leads to treat insulin resistance and diabetic nephropathy by performing high-throughput small molecule library screens on the developed transgenic fish models. The ultimate goal is to find a treatment to combat the early stages of diabetic nephropathy in humans.
Summary
Up to one third of diabetic patients develop nephropathy, a serious complication of diabetes. Microalbuminuria is the earliest sign of the complication, which may ultimately develop to end-stage renal disease requiring dialysis or a kidney transplant. Insulin resistance and metabolic syndrome are associated with an increased risk for diabetic nephropathy. Interestingly, glomerular epithelial cells or podocytes have recently been shown to be insulin responsive. Further, nephrin, a key structural component of podocytes, is essential for insulin action in these cells. Our novel findings show that adaptor protein CD2AP, an interaction partner of nephrin, associates with regulators of insulin signaling and glucose transport in glomeruli. The results suggest that nephrin and CD2AP are involved, by association with these proteins, in the regulation of insulin signaling and glucose transport in podocytes. We hypothesize that podocytes can develop insulin resistance and that disturbances in insulin response affect podocyte function and contribute to the development of diabetic nephropathy. The aim of this project is to clarify the mechanisms leading to development of insulin resistance in podocytes and to study the association between insulin resistance and the development of diabetic nephropathy. For this we will develop transgenic zebrafish and mouse models by overexpressing/knocking down insulin signaling-associated proteins specifically in podocytes. Further, we aim to identify novel drug leads to treat insulin resistance and diabetic nephropathy by performing high-throughput small molecule library screens on the developed transgenic fish models. The ultimate goal is to find a treatment to combat the early stages of diabetic nephropathy in humans.
Max ERC Funding
2 000 000 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym FUTUREGENES
Project Gene transfer techniques in the treatment of cardiovascular diseases and malignant glioma
Researcher (PI) Seppo Yla-Herttuala
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Call Details Advanced Grant (AdG), LS7, ERC-2009-AdG
Summary Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.
Summary
Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.
Max ERC Funding
2 200 000 €
Duration
Start date: 2010-06-01, End date: 2015-05-31
Project acronym HEATTRONICS
Project Mesoscopic heattronics: thermal and nonequilibrium effects and fluctuations in nanoelectronics
Researcher (PI) Tero Tapio Heikkilä
Host Institution (HI) JYVASKYLAN YLIOPISTO
Call Details Starting Grant (StG), PE3, ERC-2009-StG
Summary Few systems in nature are entirely in equilibrium. Out of equilibrium, there are heat currents, and different degrees of freedom or parts of studied systems may be described by entirely different temperatures if the concept of temperature is at all well defined. In this project we will study the emergence of the subsystem temperatures in different types of small electronic systems, and the physical phenomena associated with those temperatures. Our emphasis is on the mesoscopic effects, residing between the microscopic world of individual atoms and electrons, and the macroscopic everyday world. In particular, we will research thermometry methods, different types of relaxation, magnitudes of fluctuations and effects at high frequencies. We will explore these effects in a wide variety of systems: normal metals and superconductors, carbon nanostructures, nanoelectromechanical and spintronic systems. Besides contributing to the understanding of the fundamental properties of electronic systems, our studies are directly relevant for the development of thermal sensors and electron refrigerators. The improved understanding of the thermal phenomena will also benefit the study of almost any type of a nonlinear phenomenon in electronics, for example the research of solid-state realizations of quantum computing or the race towards quantum limited mass and force detection.
Summary
Few systems in nature are entirely in equilibrium. Out of equilibrium, there are heat currents, and different degrees of freedom or parts of studied systems may be described by entirely different temperatures if the concept of temperature is at all well defined. In this project we will study the emergence of the subsystem temperatures in different types of small electronic systems, and the physical phenomena associated with those temperatures. Our emphasis is on the mesoscopic effects, residing between the microscopic world of individual atoms and electrons, and the macroscopic everyday world. In particular, we will research thermometry methods, different types of relaxation, magnitudes of fluctuations and effects at high frequencies. We will explore these effects in a wide variety of systems: normal metals and superconductors, carbon nanostructures, nanoelectromechanical and spintronic systems. Besides contributing to the understanding of the fundamental properties of electronic systems, our studies are directly relevant for the development of thermal sensors and electron refrigerators. The improved understanding of the thermal phenomena will also benefit the study of almost any type of a nonlinear phenomenon in electronics, for example the research of solid-state realizations of quantum computing or the race towards quantum limited mass and force detection.
Max ERC Funding
1 322 371 €
Duration
Start date: 2010-01-01, End date: 2015-12-31
Project acronym ID-CAB
Project Individual differences in Collective Animal Behaviour
Researcher (PI) David Sumpter
Host Institution (HI) UPPSALA UNIVERSITET
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 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 Hammarström
Host Institution (HI) KAROLINSKA INSTITUTET
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 INSYSBIO
Project Industrial Systems Biology of Yeast and A. oryzae
Researcher (PI) Jens Nielsen
Host Institution (HI) CHALMERS TEKNISKA HOEGSKOLA AB
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
