Project acronym CARDIOPREVENT
Project INTEGRATION OF GENOMICS AND CARDIOMETABOLIC PLASMA BIOMARKERS FOR IMPROVED PREDICTION AND PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE
Researcher (PI) Olle Sten Melander
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS7, ERC-2011-StG_20101109
Summary "By taking advantage of great experience in genetic and cardiovascular epidemiology and some of the largest cohorts in the world including 60 000 unique individuals, the applicant aims at (1) improving CVD risk prediction and (2) identifying mechanisms causally related to CVD development in order to provide novel targets for drug discovery and targeted life style interventions for use in primary prevention.
In SUBPROJECT 1 we aim at identifying disease causing alleles of loci implicated in CVD by Genome Wide Association Studies (GWAS) and to identify rare alleles with large impact on human CVD. We thus perform whole exome and targeted sequencing in early CVD cases and healthy controls and evaluate all identified variants by relating them to incident CVD in 60.000 individuals. Further, we will create a score of all validated CVD gene variants and test whether such a score improves clinical risk assessment over and above traditional risk factors.
In SUBPROJECT 2 we test whether the plasma metabolome- a phenotype representing the product of dietary intake and inherent (e.g. genetic) metabolism- differs between incident CVD cases and controls and between individuals with high and low CVD genetic risk. We further test whether a life style intervention differentially alters the plasma metabolome between individuals with high and low CVD genetic risk. Finally, we will elucidate the mechanisms underlying CVD genetic associations by testing whether myocardial expression of such genes are affected by experimental myocardial infarction (MI) and whether heart function, MI size and the plasma metabolome are affected by adenoviral myocardial CVD gene transfer in rats.
In SUBPROJECT 3 we test whether glucose metabolism and CVD risk factors can be ameliorated by suppressing vasopressin (VP) by increased water intake in humans. Finally, we test which of the 3 VP receptors is responsible for adverse glucometabolic VP effects in rats by specific VP receptor pharmacological studies."
Summary
"By taking advantage of great experience in genetic and cardiovascular epidemiology and some of the largest cohorts in the world including 60 000 unique individuals, the applicant aims at (1) improving CVD risk prediction and (2) identifying mechanisms causally related to CVD development in order to provide novel targets for drug discovery and targeted life style interventions for use in primary prevention.
In SUBPROJECT 1 we aim at identifying disease causing alleles of loci implicated in CVD by Genome Wide Association Studies (GWAS) and to identify rare alleles with large impact on human CVD. We thus perform whole exome and targeted sequencing in early CVD cases and healthy controls and evaluate all identified variants by relating them to incident CVD in 60.000 individuals. Further, we will create a score of all validated CVD gene variants and test whether such a score improves clinical risk assessment over and above traditional risk factors.
In SUBPROJECT 2 we test whether the plasma metabolome- a phenotype representing the product of dietary intake and inherent (e.g. genetic) metabolism- differs between incident CVD cases and controls and between individuals with high and low CVD genetic risk. We further test whether a life style intervention differentially alters the plasma metabolome between individuals with high and low CVD genetic risk. Finally, we will elucidate the mechanisms underlying CVD genetic associations by testing whether myocardial expression of such genes are affected by experimental myocardial infarction (MI) and whether heart function, MI size and the plasma metabolome are affected by adenoviral myocardial CVD gene transfer in rats.
In SUBPROJECT 3 we test whether glucose metabolism and CVD risk factors can be ameliorated by suppressing vasopressin (VP) by increased water intake in humans. Finally, we test which of the 3 VP receptors is responsible for adverse glucometabolic VP effects in rats by specific VP receptor pharmacological studies."
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-12-01, End date: 2016-11-30
Project acronym GUTSY
Project The gut microbiota and its systemic effects on metabolism and atherosclerotic disease
Researcher (PI) Tove Elisabet FALL
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Atherosclerosis is the main pathological mechanism causing myocardial infarction and ischemic stroke. Evidence has mounted about the association between the gut microbiota and cardiovascular disease, but whether the associations are causal is largely unknown. For optimal prevention and treatment of cardiovascular disease, there is an urgent need to determine whether there are any true effects that might be targeted by interventions. The overall goal of this project is to assess causality between gut microbiota and atherosclerotic disease and to provide easily accessible biomarkers for an atherosclerosis-enhancing gut microbiota. To this end, the research program has three main objectives:
1.) Identification of gut microbiota characteristics associated with atherosclerosis measured by coronary computed tomography angiography and high-resolution carotid ultrasound in a population-based sample of 10,000 individuals and through prospective follow-up for myocardial infarction and ischemic stroke. The microbiota will be characterized by next-generation sequencing techniques in faecal samples.
2.) Identification of plasma biomarkers associated with an atherosclerosis- enhancing microbiota using comprehensive metabolomics profiling of 800 named metabolites in plasma from 800 individuals with replication in additional 800 individuals
3.) Clarification of the causal effects of gut microbiota characteristics on atherosclerosis, myocardial infarction and stroke by development of novel genetic instruments and applying Mendelian Randomization analysis
I have access to unique study materials and documented experience of successful projects using large scale -omics data and state-of-the-art epidemiological methodologies. My project is expected to lead to the identification of characteristics of an atherosclerosis-enhancing gut microbiota and associated plasma biomarkers that may open up new avenues for effective prevention of atherosclerotic disease.
Summary
Atherosclerosis is the main pathological mechanism causing myocardial infarction and ischemic stroke. Evidence has mounted about the association between the gut microbiota and cardiovascular disease, but whether the associations are causal is largely unknown. For optimal prevention and treatment of cardiovascular disease, there is an urgent need to determine whether there are any true effects that might be targeted by interventions. The overall goal of this project is to assess causality between gut microbiota and atherosclerotic disease and to provide easily accessible biomarkers for an atherosclerosis-enhancing gut microbiota. To this end, the research program has three main objectives:
1.) Identification of gut microbiota characteristics associated with atherosclerosis measured by coronary computed tomography angiography and high-resolution carotid ultrasound in a population-based sample of 10,000 individuals and through prospective follow-up for myocardial infarction and ischemic stroke. The microbiota will be characterized by next-generation sequencing techniques in faecal samples.
2.) Identification of plasma biomarkers associated with an atherosclerosis- enhancing microbiota using comprehensive metabolomics profiling of 800 named metabolites in plasma from 800 individuals with replication in additional 800 individuals
3.) Clarification of the causal effects of gut microbiota characteristics on atherosclerosis, myocardial infarction and stroke by development of novel genetic instruments and applying Mendelian Randomization analysis
I have access to unique study materials and documented experience of successful projects using large scale -omics data and state-of-the-art epidemiological methodologies. My project is expected to lead to the identification of characteristics of an atherosclerosis-enhancing gut microbiota and associated plasma biomarkers that may open up new avenues for effective prevention of atherosclerotic disease.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym INTGEN
Project Intergenerational correlations of schooling, income and health: an investigation of the underlying mechanisms
Researcher (PI) Carl Mikael Lindahl
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Starting Grant (StG), SH1, ERC-2009-StG
Summary The objective of this project is to use rich Swedish registry data to learn about mechanisms behind intergenerational correlations. Typically, considerably effort has been spent on estimating correlations between outcome variables, such as education and income, for parents and children. However, the estimated correlations are driven by the causal effect of the parental variable of interest as well as unobservable factors such as other family background related variables and a part that is due to genetic transmission between parent and child. Disentangling these parts is very difficult and only recently has researchers made serious attempts to disentangling these different parts. However, findings vary widely across methods and this literature is still in its infancy. Among questions we ask are: How much of the association between outcome variables for the child and a parent is due to a causal effect from the parental variable, and how much is transmitted through unobservable family factors and genetic transmission? What are the intergenerational transmission and channels for life expectancy and health? What is the importance of genes-environmental interaction? Has the importance of genes, environment and its interactions for the intergenerational associations changed during the growth of the Scandinavian welfare state? How many generations does it take for ancestors placement in the income distribution to not longer matter for life success? These questions are directly relevant for policy, and relate to classical social science issues such as inequality of opportunity and level-of-living in general. The innovativeness of this project is based on using the uniqueness of Swedish registry data (ideal to answer these questions), with which one can match biological and adoptive parents, children and siblings, and hence can identify whether children are reared by their biological or adoptive parents, for the population of Swedes.
Summary
The objective of this project is to use rich Swedish registry data to learn about mechanisms behind intergenerational correlations. Typically, considerably effort has been spent on estimating correlations between outcome variables, such as education and income, for parents and children. However, the estimated correlations are driven by the causal effect of the parental variable of interest as well as unobservable factors such as other family background related variables and a part that is due to genetic transmission between parent and child. Disentangling these parts is very difficult and only recently has researchers made serious attempts to disentangling these different parts. However, findings vary widely across methods and this literature is still in its infancy. Among questions we ask are: How much of the association between outcome variables for the child and a parent is due to a causal effect from the parental variable, and how much is transmitted through unobservable family factors and genetic transmission? What are the intergenerational transmission and channels for life expectancy and health? What is the importance of genes-environmental interaction? Has the importance of genes, environment and its interactions for the intergenerational associations changed during the growth of the Scandinavian welfare state? How many generations does it take for ancestors placement in the income distribution to not longer matter for life success? These questions are directly relevant for policy, and relate to classical social science issues such as inequality of opportunity and level-of-living in general. The innovativeness of this project is based on using the uniqueness of Swedish registry data (ideal to answer these questions), with which one can match biological and adoptive parents, children and siblings, and hence can identify whether children are reared by their biological or adoptive parents, for the population of Swedes.
Max ERC Funding
631 600 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym MegaALS
Project Unravelling the Interplay between Metabolism, Gut Microbiome and Adaptive Immunity in Amyotrophic Lateral Sclerosis
Researcher (PI) Fang FANG
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Amyotrophic lateral sclerosis (ALS) is a rare but devastating neurodegenerative disorder that in lack of effective treatments leads to death within a few years of diagnosis. ALS is increasingly being recognized as a systemic disease affecting not only the central nervous system but also other physiological aspects. We hypothesize that there is a disease-specific interplay between metabolism, gut microbiome and adaptive immunity, which substantially contributes to the etiopathogenesis of ALS. The overarching aim of this project is therefore to explore such interplay, and to assess the effectiveness of a treatment regimen that specifically targets it. Using a population-based case-control study of ALS in Stockholm, I will first characterize the complex interactions between metabolism, microbiome, and immunity in ALS, through comprehensive proteomic, metagenomic and immune-response profiling. The specificity of these interactions will be tested in contrast to healthy individuals at high risk for ALS (siblings), individuals with similar environmental and lifestyle factors (spouses), and unrelated population-controls. I will then use an established ALS mouse model (SOD1G93A) to understand the usefulness of combining a high-caloric diet with a fecal microbiota transplant from healthy human donors in disease prevention and treatment. To better understand the underlying mechanisms, I will compare microbiome and immune-response profiles before and after the intervention. The proposed research is unique as it 1) combines innovative molecular platforms with a high-quality epidemiological study design, 2) uses a novel strategy of investigating multiple aspects of human physiology, and 3) offers a possibility to directly translate findings between human observational and animal experimental studies. The ultimate goal is to significantly advance our knowledge about ALS as a disease, and more importantly to identify novel and highly warranted preventive and therapeutic targets.
Summary
Amyotrophic lateral sclerosis (ALS) is a rare but devastating neurodegenerative disorder that in lack of effective treatments leads to death within a few years of diagnosis. ALS is increasingly being recognized as a systemic disease affecting not only the central nervous system but also other physiological aspects. We hypothesize that there is a disease-specific interplay between metabolism, gut microbiome and adaptive immunity, which substantially contributes to the etiopathogenesis of ALS. The overarching aim of this project is therefore to explore such interplay, and to assess the effectiveness of a treatment regimen that specifically targets it. Using a population-based case-control study of ALS in Stockholm, I will first characterize the complex interactions between metabolism, microbiome, and immunity in ALS, through comprehensive proteomic, metagenomic and immune-response profiling. The specificity of these interactions will be tested in contrast to healthy individuals at high risk for ALS (siblings), individuals with similar environmental and lifestyle factors (spouses), and unrelated population-controls. I will then use an established ALS mouse model (SOD1G93A) to understand the usefulness of combining a high-caloric diet with a fecal microbiota transplant from healthy human donors in disease prevention and treatment. To better understand the underlying mechanisms, I will compare microbiome and immune-response profiles before and after the intervention. The proposed research is unique as it 1) combines innovative molecular platforms with a high-quality epidemiological study design, 2) uses a novel strategy of investigating multiple aspects of human physiology, and 3) offers a possibility to directly translate findings between human observational and animal experimental studies. The ultimate goal is to significantly advance our knowledge about ALS as a disease, and more importantly to identify novel and highly warranted preventive and therapeutic targets.
Max ERC Funding
1 499 196 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym Meiotic telomere
Project Study of telomere function in germ cells, relevant to the regulations of homologous recombination and telomere length maintenance across generations
Researcher (PI) Hiroki Shibuya
Host Institution (HI) GOETEBORGS UNIVERSITET
Call Details Starting Grant (StG), LS1, ERC-2018-STG
Summary The length of telomeric DNA is a critical determinant factor for aging and cancer development. In germ cells, the activation of a telomerase-dependent telomere-lengthening pathway is thought to be important in order to maintain telomeric DNA across generations, but the molecular mechanisms involved in this pathway, i.e: how and when telomerase is activated in germ cells, are largely unknown.
A DNA-binding protein complex called shelterin constitutively binds telomeric DNA. However, my recent studies have suggested that a multi-subunit DNA-binding complex, TERB1-TERB2-MAJIN, takes over telomeric DNA from shelterin in mammalian germ cells in order to facilitate homologous recombination. These findings represent a hitherto unknown molecular mechanism at work on the telomeres in germ cells.
In this project, I hypothesize that the drastic reformation of telomere-binding complexes in germ cells contributes also to the telomere-lengthening pathway. The aim of this project is to test this hypothesis in order to reveal the mechanism underlying the transgenerational inheritance of telomeric DNA throughout meiosis. This work is divided into three work packages.
WP1: to determine the molecular rearrangements that take place at telomeres during meiosis.
WP2: to determine how and when telomeres are lengthened during germ cell production.
WP3: to determine how meiotic recombination is achieved.
The proposed project will reveal molecular mechanisms underlying the transgenerational inheritance of genetic information after meiosis, and this will increase our understanding of the etiology of numerous human diseases caused by meiotic errors, such as congenital birth defects and aneuploidy. Further, because the misregulation of telomerase is a leading cause of cancer development, the identification of telomerase-activating mechanisms in germ cells will have multidiscipline impacts in both cancer and reproductive biology fields and will be useful for developing novel cancer therapies.
Summary
The length of telomeric DNA is a critical determinant factor for aging and cancer development. In germ cells, the activation of a telomerase-dependent telomere-lengthening pathway is thought to be important in order to maintain telomeric DNA across generations, but the molecular mechanisms involved in this pathway, i.e: how and when telomerase is activated in germ cells, are largely unknown.
A DNA-binding protein complex called shelterin constitutively binds telomeric DNA. However, my recent studies have suggested that a multi-subunit DNA-binding complex, TERB1-TERB2-MAJIN, takes over telomeric DNA from shelterin in mammalian germ cells in order to facilitate homologous recombination. These findings represent a hitherto unknown molecular mechanism at work on the telomeres in germ cells.
In this project, I hypothesize that the drastic reformation of telomere-binding complexes in germ cells contributes also to the telomere-lengthening pathway. The aim of this project is to test this hypothesis in order to reveal the mechanism underlying the transgenerational inheritance of telomeric DNA throughout meiosis. This work is divided into three work packages.
WP1: to determine the molecular rearrangements that take place at telomeres during meiosis.
WP2: to determine how and when telomeres are lengthened during germ cell production.
WP3: to determine how meiotic recombination is achieved.
The proposed project will reveal molecular mechanisms underlying the transgenerational inheritance of genetic information after meiosis, and this will increase our understanding of the etiology of numerous human diseases caused by meiotic errors, such as congenital birth defects and aneuploidy. Further, because the misregulation of telomerase is a leading cause of cancer development, the identification of telomerase-activating mechanisms in germ cells will have multidiscipline impacts in both cancer and reproductive biology fields and will be useful for developing novel cancer therapies.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym Orgasome
Project Protein synthesis in organelles
Researcher (PI) Alexey AMUNTS
Host Institution (HI) STOCKHOLMS UNIVERSITET
Call Details Starting Grant (StG), LS1, ERC-2018-STG
Summary Protein synthesis in mitochondria is essential for the bioenergetics, whereas its counterpart in chloroplasts is responsible for the synthesis of the core proteins that ultimately converts sunlight into the chemical energy that produces oxygen and organic matter. Recent insights into the mito- and chlororibosomes have provided the first glimpses into the distinct and specialized machineries that involved in synthesizing almost exclusively hydrophobic membrane proteins. Our findings showed: 1) mitoribosomes have different exit tunnels, intrinsic GTPase in the head of the small subunit, tRNA-Val incorporated into the central protuberance; 2) chlororibosomes have divaricate tunnels; 3) ribosomes from both organelles exhibit parallel evolution. This allows contemplation of questions regarding the next level of complexity: How these ribosomes work and evolve? How the ribosomal components imported from cytosol are assembled with the organellar rRNA into a functional unit being maturated in different compartments in organelles? Which trans-factors are involved in this process? How the chlororibosomal activity is spatiotemporally coupled to the synthesis and incorporation of functionally essential pigments? What are the specific regulatory mechanisms?
To address these questions, there is a need to first to characterize the process of translation in organelles on the structural level. To reveal molecular mechanisms of action, we will use antibiotics and mutants for pausing in different stages. To reconstitute the assembly, we will systematically pull-down pre-ribosomes and combine single particle with tomography to put the dynamic process in the context of the whole organelle. To understand co-translational operations, we will stall ribosomes and characterize their partner factors. To elucidate the evolution, we will analyze samples from different species.
Taken together, this will provide fundamental insights into the structural and functional dynamics of organelles.
Summary
Protein synthesis in mitochondria is essential for the bioenergetics, whereas its counterpart in chloroplasts is responsible for the synthesis of the core proteins that ultimately converts sunlight into the chemical energy that produces oxygen and organic matter. Recent insights into the mito- and chlororibosomes have provided the first glimpses into the distinct and specialized machineries that involved in synthesizing almost exclusively hydrophobic membrane proteins. Our findings showed: 1) mitoribosomes have different exit tunnels, intrinsic GTPase in the head of the small subunit, tRNA-Val incorporated into the central protuberance; 2) chlororibosomes have divaricate tunnels; 3) ribosomes from both organelles exhibit parallel evolution. This allows contemplation of questions regarding the next level of complexity: How these ribosomes work and evolve? How the ribosomal components imported from cytosol are assembled with the organellar rRNA into a functional unit being maturated in different compartments in organelles? Which trans-factors are involved in this process? How the chlororibosomal activity is spatiotemporally coupled to the synthesis and incorporation of functionally essential pigments? What are the specific regulatory mechanisms?
To address these questions, there is a need to first to characterize the process of translation in organelles on the structural level. To reveal molecular mechanisms of action, we will use antibiotics and mutants for pausing in different stages. To reconstitute the assembly, we will systematically pull-down pre-ribosomes and combine single particle with tomography to put the dynamic process in the context of the whole organelle. To understand co-translational operations, we will stall ribosomes and characterize their partner factors. To elucidate the evolution, we will analyze samples from different species.
Taken together, this will provide fundamental insights into the structural and functional dynamics of organelles.
Max ERC Funding
1 331 300 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym PATER
Project Paternal Epigenetic Inheritance: A man’s life experiences may impact health of his unborn children and grandchildren
Researcher (PI) Mats Oskar KARLSSON
Host Institution (HI) STOCKHOLMS UNIVERSITET
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Epigenetic inheritance may not only occur in plants and fungi but also in mammals. While the effect of maternal lifestyle and in utero exposures is well studied, paternal epigenetic inheritance is a novel research field, especially in regard to chemical exposures. Many environmental pollutants exhibit anti-androgenic function. Despite the vital role of androgens in spermatogenesis, the effects of adult anti-androgen exposure on the sperm epigenome and offspring phenotype have been scarcely studied.
The overall aim of this novel project is to increase the understanding of if, and how, male life experiences such as adult exposure to the anti-androgenic model substance and pollutant DBP (di-n-butyl phthalate) may affect offspring through paternal epigenetic inheritance. I accomplish this by integrating animal and human studies, using RNA-sequencing and mass spectrometry-based peptidomics to identify DBP-induced alterations in the sperm transcriptome and peptidome, examine noncoding RNAs and peptides role in embryogenesis, development and long-term health of the offspring in two generations. To validate the mechanistic importance of the sperm molecular alterations microinjections of selected biomolecules into zygotes will be conducted. This is the first project to investigate multigenerational effects of adult male exposure to anti-androgens in detail, and investigate the role of the sperm peptidome in paternal epigenetic inheritance. Directly linking animal experimental data about paternal transmission to human studies is unique and necessary to determine causal connection between environmentally-induced biomolecular alterations in sperm and offspring phenotype. The project can contribute to ground-breaking mechanistic understanding of how male life experiences may affect offspring through epigenetic inheritance. The findings may also have important public health implications via new regulations of anti-androgenic chemicals and male preconceptional interventions.
Summary
Epigenetic inheritance may not only occur in plants and fungi but also in mammals. While the effect of maternal lifestyle and in utero exposures is well studied, paternal epigenetic inheritance is a novel research field, especially in regard to chemical exposures. Many environmental pollutants exhibit anti-androgenic function. Despite the vital role of androgens in spermatogenesis, the effects of adult anti-androgen exposure on the sperm epigenome and offspring phenotype have been scarcely studied.
The overall aim of this novel project is to increase the understanding of if, and how, male life experiences such as adult exposure to the anti-androgenic model substance and pollutant DBP (di-n-butyl phthalate) may affect offspring through paternal epigenetic inheritance. I accomplish this by integrating animal and human studies, using RNA-sequencing and mass spectrometry-based peptidomics to identify DBP-induced alterations in the sperm transcriptome and peptidome, examine noncoding RNAs and peptides role in embryogenesis, development and long-term health of the offspring in two generations. To validate the mechanistic importance of the sperm molecular alterations microinjections of selected biomolecules into zygotes will be conducted. This is the first project to investigate multigenerational effects of adult male exposure to anti-androgens in detail, and investigate the role of the sperm peptidome in paternal epigenetic inheritance. Directly linking animal experimental data about paternal transmission to human studies is unique and necessary to determine causal connection between environmentally-induced biomolecular alterations in sperm and offspring phenotype. The project can contribute to ground-breaking mechanistic understanding of how male life experiences may affect offspring through epigenetic inheritance. The findings may also have important public health implications via new regulations of anti-androgenic chemicals and male preconceptional interventions.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
