Project acronym ANGIOFAT
Project New mechanisms of angiogenesis modulators in switching between white and brown adipose tissues
Researcher (PI) Yihai Cao
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS4, ERC-2009-AdG
Summary Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.
Summary
Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.
Max ERC Funding
2 411 547 €
Duration
Start date: 2010-03-01, End date: 2015-02-28
Project acronym ASD
Project Atomistic Spin-Dynamics; Methodology and Applications
Researcher (PI) Olof Ragnar Eriksson
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
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 BBBARRIER
Project Mechanisms of regulation of the blood-brain barrier; towards opening and closing the barrier on demand
Researcher (PI) Bjoern Christer Betsholtz
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), LS4, ERC-2011-ADG_20110310
Summary In the bone-enclosed CNS, increased vascular permeability may cause life-threatening tissue swelling, and/or ischemia and inflammation which compromise tissue repair after trauma or stroke. The brain vasculature possesses several unique features collectively named the blood-brain barrier (BBB) in which passive permeability is almost completely abolished and replaced by a complex of specific transport mechanisms. The BBB is necessary to uphold the specific milieu necessary for neuronal function. Whereas breakdown of the BBB is part of many CNS diseases, including stroke, neuroinflammation, trauma and neurodegenerative disorders, its molecular mechanisms and consequences are unclear and debated. Conversely, the intact BBB is a huge obstacle for drug delivery to the brain. Research on the BBB therefore has two seemingly opposing aims: 1) to seal a damaged BBB and protect the brain from toxic blood products, and 2) to open the BBB “on demand” for drug delivery. A major problem in the BBB field has been the lack of in vivo animal models for molecular and functional studies. So far, available in vitro models are not recapitulating the in vivo BBB. Our recent work on mouse models lacking pericytes, a BBB-associated cell type, demonstrates a specific role for pericytes in the development and regulation of the mammalian BBB. These animal models are the first ones showing a general and significant BBB impairment in adulthood, and as such they provide a unique opportunity to address molecular mechanisms of BBB disruption in disease and in drug transport across the BBB. Importantly, the new models and tools that we have developed allow us to search for relevant druggable mechanisms and molecular targets in the BBB. The long-term goals of this proposal are to develop molecular strategies and tools to open and close the BBB “on demand” for drug delivery to the CNS, and to explore the importance and mechanisms of BBB dysfunction in neurodegenerative diseases and stroke.
Summary
In the bone-enclosed CNS, increased vascular permeability may cause life-threatening tissue swelling, and/or ischemia and inflammation which compromise tissue repair after trauma or stroke. The brain vasculature possesses several unique features collectively named the blood-brain barrier (BBB) in which passive permeability is almost completely abolished and replaced by a complex of specific transport mechanisms. The BBB is necessary to uphold the specific milieu necessary for neuronal function. Whereas breakdown of the BBB is part of many CNS diseases, including stroke, neuroinflammation, trauma and neurodegenerative disorders, its molecular mechanisms and consequences are unclear and debated. Conversely, the intact BBB is a huge obstacle for drug delivery to the brain. Research on the BBB therefore has two seemingly opposing aims: 1) to seal a damaged BBB and protect the brain from toxic blood products, and 2) to open the BBB “on demand” for drug delivery. A major problem in the BBB field has been the lack of in vivo animal models for molecular and functional studies. So far, available in vitro models are not recapitulating the in vivo BBB. Our recent work on mouse models lacking pericytes, a BBB-associated cell type, demonstrates a specific role for pericytes in the development and regulation of the mammalian BBB. These animal models are the first ones showing a general and significant BBB impairment in adulthood, and as such they provide a unique opportunity to address molecular mechanisms of BBB disruption in disease and in drug transport across the BBB. Importantly, the new models and tools that we have developed allow us to search for relevant druggable mechanisms and molecular targets in the BBB. The long-term goals of this proposal are to develop molecular strategies and tools to open and close the BBB “on demand” for drug delivery to the CNS, and to explore the importance and mechanisms of BBB dysfunction in neurodegenerative diseases and stroke.
Max ERC Funding
2 499 427 €
Duration
Start date: 2012-08-01, End date: 2017-07-31
Project acronym BETAIMAGE
Project An in vivo imaging approach to understand pancreatic beta-cell signal-transduction
Researcher (PI) Per-Olof Berggren
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary The challenge in cell physiology/pathology today is to translate in vitro findings to the living organism. We have developed a unique approach where signal-transduction can be investigated in vivo non-invasively, longitudinally at single cell resolution, using the anterior chamber of the eye as a natural body window for imaging. We will use this approach to understand how the universally important and highly complex signal Ca2+ is regulated in the pancreatic beta-cell, while localized in the vascularized and innervated islet of Langerhans, and how that affects the insulin secretory machinery in vivo. Engrafted islets in the eye take on identical innervation- and vascularization patterns as those in the pancreas and are proficient in regulating glucose homeostasis in the animal. Since the pancreatic islet constitutes a micro-organ, this imaging approach offers a seminal model system to understand Ca2+ signaling in individual cells at the organ level in real life. We will test the hypothesis that the Ca2+-signal has a key role in pancreatic beta-cell function and survival in vivo and that perturbation in the Ca2+-signal serves as a common denominator for beta-cell pathology associated with impaired glucose homeostasis and diabetes. Of special interest is how innervation impacts on Ca2+-dynamics and the integration of autocrine, paracrine and endocrine signals in fine-tuning the Ca2+-signal with regard to beta-cell function and survival. We aim to define key defects in the machinery regulating Ca2+-dynamics in association with the autoimmune reaction, inflammation and obesity eventually resulting in diabetes. Our imaging platform will be applied to clarify in vivo regulation of Ca2+-dynamics in both healthy and diabetic human beta-cells. To define novel drugable targets for treatment of diabetes, it is crucial to identify similarities and differences in the molecular machinery regulating the in vivo Ca2+-signal in the human and in the rodent beta-cell.
Summary
The challenge in cell physiology/pathology today is to translate in vitro findings to the living organism. We have developed a unique approach where signal-transduction can be investigated in vivo non-invasively, longitudinally at single cell resolution, using the anterior chamber of the eye as a natural body window for imaging. We will use this approach to understand how the universally important and highly complex signal Ca2+ is regulated in the pancreatic beta-cell, while localized in the vascularized and innervated islet of Langerhans, and how that affects the insulin secretory machinery in vivo. Engrafted islets in the eye take on identical innervation- and vascularization patterns as those in the pancreas and are proficient in regulating glucose homeostasis in the animal. Since the pancreatic islet constitutes a micro-organ, this imaging approach offers a seminal model system to understand Ca2+ signaling in individual cells at the organ level in real life. We will test the hypothesis that the Ca2+-signal has a key role in pancreatic beta-cell function and survival in vivo and that perturbation in the Ca2+-signal serves as a common denominator for beta-cell pathology associated with impaired glucose homeostasis and diabetes. Of special interest is how innervation impacts on Ca2+-dynamics and the integration of autocrine, paracrine and endocrine signals in fine-tuning the Ca2+-signal with regard to beta-cell function and survival. We aim to define key defects in the machinery regulating Ca2+-dynamics in association with the autoimmune reaction, inflammation and obesity eventually resulting in diabetes. Our imaging platform will be applied to clarify in vivo regulation of Ca2+-dynamics in both healthy and diabetic human beta-cells. To define novel drugable targets for treatment of diabetes, it is crucial to identify similarities and differences in the molecular machinery regulating the in vivo Ca2+-signal in the human and in the rodent beta-cell.
Max ERC Funding
2 499 590 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym COMPASS
Project Colloids with complex interactions: from model atoms to colloidal recognition and bio-inspired self assembly
Researcher (PI) Peter Schurtenberger
Host Institution (HI) MAX IV Laboratory, Lund University
Country Sweden
Call Details Advanced Grant (AdG), PE3, ERC-2013-ADG
Summary Self-assembly is the key construction principle that nature uses so successfully to fabricate its molecular machinery and highly elaborate structures. In this project we will follow nature’s strategies and make a concerted experimental and theoretical effort to study, understand and control self-assembly for a new generation of colloidal building blocks. Starting point will be recent advances in colloid synthesis strategies that have led to a spectacular array of colloids of different shapes, compositions, patterns and functionalities. These allow us to investigate the influence of anisotropy in shape and interactions on aggregation and self-assembly in colloidal suspensions and mixtures. Using responsive particles we will implement colloidal lock-and-key mechanisms and then assemble a library of “colloidal molecules” with well-defined and externally tunable binding sites using microfluidics-based and externally controlled fabrication and sorting principles. We will use them to explore the equilibrium phase behavior of particle systems interacting through a finite number of binding sites. In parallel, we will exploit them and investigate colloid self-assembly into well-defined nanostructures. Here we aim at achieving much more refined control than currently possible by implementing a protein-inspired approach to controlled self-assembly. We combine molecule-like colloidal building blocks that possess directional interactions and externally triggerable specific recognition sites with directed self-assembly where external fields not only facilitate assembly, but also allow fabricating novel structures. We will use the tunable combination of different contributions to the interaction potential between the colloidal building blocks and the ability to create chirality in the assembly to establish the requirements for the controlled formation of tubular shells and thus create a colloid-based minimal model of synthetic virus capsid proteins.
Summary
Self-assembly is the key construction principle that nature uses so successfully to fabricate its molecular machinery and highly elaborate structures. In this project we will follow nature’s strategies and make a concerted experimental and theoretical effort to study, understand and control self-assembly for a new generation of colloidal building blocks. Starting point will be recent advances in colloid synthesis strategies that have led to a spectacular array of colloids of different shapes, compositions, patterns and functionalities. These allow us to investigate the influence of anisotropy in shape and interactions on aggregation and self-assembly in colloidal suspensions and mixtures. Using responsive particles we will implement colloidal lock-and-key mechanisms and then assemble a library of “colloidal molecules” with well-defined and externally tunable binding sites using microfluidics-based and externally controlled fabrication and sorting principles. We will use them to explore the equilibrium phase behavior of particle systems interacting through a finite number of binding sites. In parallel, we will exploit them and investigate colloid self-assembly into well-defined nanostructures. Here we aim at achieving much more refined control than currently possible by implementing a protein-inspired approach to controlled self-assembly. We combine molecule-like colloidal building blocks that possess directional interactions and externally triggerable specific recognition sites with directed self-assembly where external fields not only facilitate assembly, but also allow fabricating novel structures. We will use the tunable combination of different contributions to the interaction potential between the colloidal building blocks and the ability to create chirality in the assembly to establish the requirements for the controlled formation of tubular shells and thus create a colloid-based minimal model of synthetic virus capsid proteins.
Max ERC Funding
2 498 040 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym CUSTOMER
Project Customizable Embedded Real-Time Systems: Challenges and Key Techniques
Researcher (PI) Yi WANG
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), PE6, ERC-2018-ADG
Summary Today, many industrial products are defined by software and therefore customizable: their functionalities implemented by software can be modified and extended by dynamic software updates on demand. This trend towards customizable products is rapidly expanding into all domains of IT, including Embedded Real-Time Systems (ERTS) deployed in Cyber-Physical Systems such as cars, medical devices etc. However, the current state-of-practice in safety-critical systems allows hardly any modifications once they are put in operation. The lack of techniques to preserve crucial safety conditions for customizable systems severely restricts the benefits of advances in software-defined systems engineering.
CUSTOMER is to provide the missing paradigm and technology for building and updating ERTS after deployment – subject to stringent timing constraints, dynamic workloads, and limited resources on complex platforms. CUSTOMER explores research areas crossing two fields: Real-Time Computing and Formal Verification to develop the key techniques enabling (1) dynamic updates of ERTS in the field, (2) incremental updates over the products life time and (3) safe updates by verification to avoid updates that may compromise system safety.
CUSTOMER will develop a unified model-based framework supported with tools for the design, modelling, verification, deployment and update of ERTS, aiming at advancing the research fields by establishing the missing scientific foundation for multiprocessor real-time computing and providing the next generation of design tools with significantly enhanced capability and scalability increased by orders of magnitude compared with state-of-the-art tools e.g. UPPAAL.
Summary
Today, many industrial products are defined by software and therefore customizable: their functionalities implemented by software can be modified and extended by dynamic software updates on demand. This trend towards customizable products is rapidly expanding into all domains of IT, including Embedded Real-Time Systems (ERTS) deployed in Cyber-Physical Systems such as cars, medical devices etc. However, the current state-of-practice in safety-critical systems allows hardly any modifications once they are put in operation. The lack of techniques to preserve crucial safety conditions for customizable systems severely restricts the benefits of advances in software-defined systems engineering.
CUSTOMER is to provide the missing paradigm and technology for building and updating ERTS after deployment – subject to stringent timing constraints, dynamic workloads, and limited resources on complex platforms. CUSTOMER explores research areas crossing two fields: Real-Time Computing and Formal Verification to develop the key techniques enabling (1) dynamic updates of ERTS in the field, (2) incremental updates over the products life time and (3) safe updates by verification to avoid updates that may compromise system safety.
CUSTOMER will develop a unified model-based framework supported with tools for the design, modelling, verification, deployment and update of ERTS, aiming at advancing the research fields by establishing the missing scientific foundation for multiprocessor real-time computing and providing the next generation of design tools with significantly enhanced capability and scalability increased by orders of magnitude compared with state-of-the-art tools e.g. UPPAAL.
Max ERC Funding
2 499 894 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym ECOSOCPOL
Project Social and Political Economics: Theory and Evidence
Researcher (PI) Torsten Persson
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), SH1, ERC-2015-AdG
Summary In this project, I will study how individual and social motives interact to drive individual decisions, a question that has fallen between the cracks of different social-science approaches. I will use a common theoretical framework to approach an important, but badly understood, general question: do social motives reinforce or weaken the effect of changes in individual motives? By modifying this common framework to different applications, I will consider its predictions empirically in different large data sets with individual-level information. The planned applications include four subprojects in the social, political, and economic spheres: (i) decisions in China on the ethnicity of children in interethnic marriages and matching into such marriages, (ii) decisions on tax evasion in the U.K. and Sweden, (iii) decisions to give political campaign contributions in the U.S., and (iv) decisions about fertility in Sweden. I may also spell out the common lessons from the results on the interaction between individual and social motives in monograph format intended for a broader audience.
Summary
In this project, I will study how individual and social motives interact to drive individual decisions, a question that has fallen between the cracks of different social-science approaches. I will use a common theoretical framework to approach an important, but badly understood, general question: do social motives reinforce or weaken the effect of changes in individual motives? By modifying this common framework to different applications, I will consider its predictions empirically in different large data sets with individual-level information. The planned applications include four subprojects in the social, political, and economic spheres: (i) decisions in China on the ethnicity of children in interethnic marriages and matching into such marriages, (ii) decisions on tax evasion in the U.K. and Sweden, (iii) decisions to give political campaign contributions in the U.S., and (iv) decisions about fertility in Sweden. I may also spell out the common lessons from the results on the interaction between individual and social motives in monograph format intended for a broader audience.
Max ERC Funding
1 104 812 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
Project acronym EYELETS
Project A regenerative medicine approach in diabetes.
Researcher (PI) Per-Olof BERGGREN
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary Pancreatic islet transplantation is essential for diabetes treatment. Outcome varies due to transplantation site, quality of islets and the fact that transplanted islets are affected by the same challenges as in situ islets. Tailor-making islets for transplantation by tissue engineering combined with a more favorable transplantation site that allows for both monitoring and local modulation of islet cells is thus instrumental. We have established the anterior chamber of the eye (ACE) as a favorable environment for long term survival of islet grafts and the cornea as a natural body window for non-invasive, longitudinal optical monitoring of islet function. ACE engrafted islets are able to maintain blood glucose homeostasis in diabetic animals. In addition to studies in non-human primates we are performing human clinical trials, the first patient already being transplanted. Tissue engineering of native islets is technically difficult. We will therefore apply genetically engineered islet organoids. This allows us to generate i) standardized material optimized for transplantation, function and survival, as well as ii) islet organoids suitable for monitoring (sensor islet organoids) and treating (metabolic islet organoids) insulin-dependent diabetes. We hypothesize that genetically engineered islet organoids transplanted to the ACE are superior to native pancreatic islets to monitor and treat insulin-dependent diabetes. Our overall aim is to create a platform allowing monitoring and treatment of insulin-dependent diabetes in mice that can be transferred to large animals for validation. The objective is to combine tissue engineering of islet cell organoids, transplantation to the ACE, synthetic biology, local pharmacological treatment strategies and the development of novel micro electronic/micro optical readout systems for islet cells. This regenerative medicine approach will follow our clinical trial programs and be transferred into the clinic to combat diabetes.
Summary
Pancreatic islet transplantation is essential for diabetes treatment. Outcome varies due to transplantation site, quality of islets and the fact that transplanted islets are affected by the same challenges as in situ islets. Tailor-making islets for transplantation by tissue engineering combined with a more favorable transplantation site that allows for both monitoring and local modulation of islet cells is thus instrumental. We have established the anterior chamber of the eye (ACE) as a favorable environment for long term survival of islet grafts and the cornea as a natural body window for non-invasive, longitudinal optical monitoring of islet function. ACE engrafted islets are able to maintain blood glucose homeostasis in diabetic animals. In addition to studies in non-human primates we are performing human clinical trials, the first patient already being transplanted. Tissue engineering of native islets is technically difficult. We will therefore apply genetically engineered islet organoids. This allows us to generate i) standardized material optimized for transplantation, function and survival, as well as ii) islet organoids suitable for monitoring (sensor islet organoids) and treating (metabolic islet organoids) insulin-dependent diabetes. We hypothesize that genetically engineered islet organoids transplanted to the ACE are superior to native pancreatic islets to monitor and treat insulin-dependent diabetes. Our overall aim is to create a platform allowing monitoring and treatment of insulin-dependent diabetes in mice that can be transferred to large animals for validation. The objective is to combine tissue engineering of islet cell organoids, transplantation to the ACE, synthetic biology, local pharmacological treatment strategies and the development of novel micro electronic/micro optical readout systems for islet cells. This regenerative medicine approach will follow our clinical trial programs and be transferred into the clinic to combat diabetes.
Max ERC Funding
2 500 000 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym GENCON
Project The evolutionary implications of genetic conflict
Researcher (PI) Goeran Arnqvist
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Advanced Grant (AdG), LS8, ERC-2011-ADG_20110310
Summary The study of genetic conflict is developing at an almost explosive rate. The recognition that genes or alleles residing in individuals of the two sexes may have conflicting interests is transforming evolutionary biology and, likewise, conflict between genes showing different modes of transmission may fundamentally affect adaptive evolution. The research proposed here will push the frontiers of genetic conflict research and establish new domains. It is aimed at exploring the novel possibility that conflict between mitochondrial and nuclear genes have far-reaching implications for adaptive evolution and at advancing our understanding of the biological consequences of sexual conflict. The project consists of several interrelated parts and will employ insects as model systems. First, I will assess to what extent genetic variation in fitness is sexually antagonistic and what life history traits contribute to sexually antagonistic variation. Second, I will elucidate the genomics of metabolic rate and measure selection on metabolic phenotypes. Third, I will test whether sexually antagonistic epistatic interactions between mitochondrial and nuclear genes generate conflict over metabolic rate. Fourth, I will test the hypothesis that sexual conflict contribute to the evolution of primary and secondary sexual traits. Fifth, I will shed light on the complicated evolutionary interplay between sexual conflict and mating system evolution. I will employ an innovative research strategy, ‘experimental genomics’, in which genomic data is used to guide experimental evolutionary work with distinct genotypes. The research outlined here will collectively provide an unprecedented wealth of information into the role of genetic conflict in several horizons of adaptive evolution, ranging from DNA sequence evolution over life history evolution to speciation, and will set the standard for a new generation of insightful studies aimed at bridging the gap between phenotypic selection and genomics.
Summary
The study of genetic conflict is developing at an almost explosive rate. The recognition that genes or alleles residing in individuals of the two sexes may have conflicting interests is transforming evolutionary biology and, likewise, conflict between genes showing different modes of transmission may fundamentally affect adaptive evolution. The research proposed here will push the frontiers of genetic conflict research and establish new domains. It is aimed at exploring the novel possibility that conflict between mitochondrial and nuclear genes have far-reaching implications for adaptive evolution and at advancing our understanding of the biological consequences of sexual conflict. The project consists of several interrelated parts and will employ insects as model systems. First, I will assess to what extent genetic variation in fitness is sexually antagonistic and what life history traits contribute to sexually antagonistic variation. Second, I will elucidate the genomics of metabolic rate and measure selection on metabolic phenotypes. Third, I will test whether sexually antagonistic epistatic interactions between mitochondrial and nuclear genes generate conflict over metabolic rate. Fourth, I will test the hypothesis that sexual conflict contribute to the evolution of primary and secondary sexual traits. Fifth, I will shed light on the complicated evolutionary interplay between sexual conflict and mating system evolution. I will employ an innovative research strategy, ‘experimental genomics’, in which genomic data is used to guide experimental evolutionary work with distinct genotypes. The research outlined here will collectively provide an unprecedented wealth of information into the role of genetic conflict in several horizons of adaptive evolution, ranging from DNA sequence evolution over life history evolution to speciation, and will set the standard for a new generation of insightful studies aimed at bridging the gap between phenotypic selection and genomics.
Max ERC Funding
2 497 442 €
Duration
Start date: 2012-05-01, End date: 2017-04-30
Project acronym GENE TARGET T2D
Project General and targeted approaches to unravel the molecular causes of type 2 diabetes
Researcher (PI) Leif Christer Groop
Host Institution (HI) MAX IV Laboratory, Lund University
Country Sweden
Call Details Advanced Grant (AdG), LS4, ERC-2010-AdG_20100317
Summary Type 2 diabetes (T2D) affects worldwide at present about 250 million patients and an estimated 380 million in 2025. This epidemic has been ascribed to a collision between genes and an affluent society. Genetics of T2D has during recent years identified > 30 variants increasing susceptibility to T2D. Yet, these variants explain only 15% of the heritability of T2D. One reason could be that whole genome association studies can only detect common variants whereas identification of rare variants with stronger effects would require sequencing. A large part of this application is devoted to sequencing of affected family members from unique large pedigrees traced back to common ancestors around 1600. The advantage of using families is that identified variants can be tested for segregation with the trait. Genetic variants can influence expression of a gene in an allele specific manner. This will be explored by combining exome sequencing with sequencing of RNA from human islets.
Impaired effects of the incretin hormones GLP-1 and GIP on the pancreatic islets represent central defects in T2D. Variants in the TCF7L2 and GIPR genes contribute to these defects. I will here explore the molecular mechanisms by which TCF7L2, the strongest T2D gene, causes T2D. GIP has unprecedented effects not only on islet function but also on body composition, blood flow and vascular complications in T2D. This application explores these effects and will test whether manipulation of GIP can mimic the normalization of glucose tolerance seen after gastric bypass surgery.
Taken together, these general and targeted approaches are expected not only to provide new insights into the causes of T2D but also contribute with vital information for development of new treatments for T2D.
Summary
Type 2 diabetes (T2D) affects worldwide at present about 250 million patients and an estimated 380 million in 2025. This epidemic has been ascribed to a collision between genes and an affluent society. Genetics of T2D has during recent years identified > 30 variants increasing susceptibility to T2D. Yet, these variants explain only 15% of the heritability of T2D. One reason could be that whole genome association studies can only detect common variants whereas identification of rare variants with stronger effects would require sequencing. A large part of this application is devoted to sequencing of affected family members from unique large pedigrees traced back to common ancestors around 1600. The advantage of using families is that identified variants can be tested for segregation with the trait. Genetic variants can influence expression of a gene in an allele specific manner. This will be explored by combining exome sequencing with sequencing of RNA from human islets.
Impaired effects of the incretin hormones GLP-1 and GIP on the pancreatic islets represent central defects in T2D. Variants in the TCF7L2 and GIPR genes contribute to these defects. I will here explore the molecular mechanisms by which TCF7L2, the strongest T2D gene, causes T2D. GIP has unprecedented effects not only on islet function but also on body composition, blood flow and vascular complications in T2D. This application explores these effects and will test whether manipulation of GIP can mimic the normalization of glucose tolerance seen after gastric bypass surgery.
Taken together, these general and targeted approaches are expected not only to provide new insights into the causes of T2D but also contribute with vital information for development of new treatments for T2D.
Max ERC Funding
2 499 480 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
