Project acronym Born-Immune
Project Shaping of the Human Immune System by Primal Environmental Exposures In the Newborn Child
Researcher (PI) Klas Erik Petter Brodin
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS6, ERC-2015-STG
Summary Immune systems are highly variable, but the sources of this variation are poorly understood. Genetic variation only explains a minor fraction of this, and we are unable to accurately predict the risk of immune mediated disease or severe infection in any given individual. I recently found that immune cells and proteins in healthy twins vary because of non-heritable influences (infections, vaccines, microbiota etc.), with only minor influences from heritable factors (Brodin, et al, Cell 2015). When and how such environmental influences shape our immune system is now important to understand. Birth represents the most transformational change in environment during the life of any individual. I propose, that environmental influences at birth, and during the first months of life could be particularly influential by imprinting on the regulatory mechanisms forming in the developing immune system. Adaptive changes in immune cell frequencies and functional states induced by early-life exposures could determine both the immune competence of the newborn, but potentially also its long-term trajectory towards immunological health or disease. Here, I propose a study of 1000 newborn children, followed longitudinally during their first 1000 days of life. By monitoring immune profiles and recording many environmental influences, we hope to understand how early life exposures can influence human immune system development. We have established a new assay based on Mass Cytometry and necessary data analysis tools (Brodin, et al, PNAS 2014), to simultaneously monitor the frequencies, phenotypes and functional states of more than 200 blood immune cell populations from only 100 microliters of blood. By monitoring environmental influences at regular follow-up visits, by questionnaires, serum measurements of infection, and gut microbiome sequencing, we aim to provide the most comprehensive analysis to date of immune system development in newborn children.
Summary
Immune systems are highly variable, but the sources of this variation are poorly understood. Genetic variation only explains a minor fraction of this, and we are unable to accurately predict the risk of immune mediated disease or severe infection in any given individual. I recently found that immune cells and proteins in healthy twins vary because of non-heritable influences (infections, vaccines, microbiota etc.), with only minor influences from heritable factors (Brodin, et al, Cell 2015). When and how such environmental influences shape our immune system is now important to understand. Birth represents the most transformational change in environment during the life of any individual. I propose, that environmental influences at birth, and during the first months of life could be particularly influential by imprinting on the regulatory mechanisms forming in the developing immune system. Adaptive changes in immune cell frequencies and functional states induced by early-life exposures could determine both the immune competence of the newborn, but potentially also its long-term trajectory towards immunological health or disease. Here, I propose a study of 1000 newborn children, followed longitudinally during their first 1000 days of life. By monitoring immune profiles and recording many environmental influences, we hope to understand how early life exposures can influence human immune system development. We have established a new assay based on Mass Cytometry and necessary data analysis tools (Brodin, et al, PNAS 2014), to simultaneously monitor the frequencies, phenotypes and functional states of more than 200 blood immune cell populations from only 100 microliters of blood. By monitoring environmental influences at regular follow-up visits, by questionnaires, serum measurements of infection, and gut microbiome sequencing, we aim to provide the most comprehensive analysis to date of immune system development in newborn children.
Max ERC Funding
1 422 339 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym ChemBioAP
Project Elucidation of autophagy using novel chemical probes
Researcher (PI) Yaowen Wu
Host Institution (HI) UMEA UNIVERSITET
Call Details Starting Grant (StG), LS1, ERC-2015-STG
Summary The interest on autophagy, an evolutionarily conserved process in eukaryotes, has enormously increased in the last years, since autophagy is involved in many diseases such as cancer and neurodegenerative disorders. Autophagosome formation is the key process in autophagy. Despite extensive work, the model of autophagosome formation is not yet well established. Some important questions on autophagosome biogenesis remain to be elusive, such as where the bona fide marker protein of autophagosome, LC3, is lipidated, how lipidated LC3 functions in autophagosome formation, and how the proteins for LC3 lipidation and delipidation are involved in autophagosome formation. Although genetic approaches have been useful to identify genes involved in autophagy, they are chronic and thereby the dynamics of phenotypic change cannot be followed, making them not suited for study highly dynamic process such as autophagosome formation. Herein, I propose to develop and use novel chemical probes to address these issues. First, I plan to prepare semi-synthetic caged LC3 proteins and apply them to monitor dynamics of autophagosome formation in the cell in order to address those questions on autophagosome formation. The semi-synthetic LC3 proteins are expected to confer a temporal control and to realize manipulation of protein structure, which renders such studies possible. Second, I intend to develop a versatile approach targeting specific endogenous proteins using a reversible chemically induced dimerization (CID) system, termed as “knock on and off” strategy. I plan to use this approach to elucidate the function of two distinct PI3K complexes in autophagosome formation. On one hand, the establishment of novel approaches will open up a new avenue for studying biological processes. On the other hand, the use of the tool will reveal the mechanism of autophagy.
Summary
The interest on autophagy, an evolutionarily conserved process in eukaryotes, has enormously increased in the last years, since autophagy is involved in many diseases such as cancer and neurodegenerative disorders. Autophagosome formation is the key process in autophagy. Despite extensive work, the model of autophagosome formation is not yet well established. Some important questions on autophagosome biogenesis remain to be elusive, such as where the bona fide marker protein of autophagosome, LC3, is lipidated, how lipidated LC3 functions in autophagosome formation, and how the proteins for LC3 lipidation and delipidation are involved in autophagosome formation. Although genetic approaches have been useful to identify genes involved in autophagy, they are chronic and thereby the dynamics of phenotypic change cannot be followed, making them not suited for study highly dynamic process such as autophagosome formation. Herein, I propose to develop and use novel chemical probes to address these issues. First, I plan to prepare semi-synthetic caged LC3 proteins and apply them to monitor dynamics of autophagosome formation in the cell in order to address those questions on autophagosome formation. The semi-synthetic LC3 proteins are expected to confer a temporal control and to realize manipulation of protein structure, which renders such studies possible. Second, I intend to develop a versatile approach targeting specific endogenous proteins using a reversible chemically induced dimerization (CID) system, termed as “knock on and off” strategy. I plan to use this approach to elucidate the function of two distinct PI3K complexes in autophagosome formation. On one hand, the establishment of novel approaches will open up a new avenue for studying biological processes. On the other hand, the use of the tool will reveal the mechanism of autophagy.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym ComplexSex
Project Sex-limited experimental evolution of natural and novel sex chromosomes: the role of sex in shaping complex traits
Researcher (PI) Jessica Abbott
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS8, ERC-2015-STG
Summary The origin and evolution of sexual reproduction and sex differences represents one of the major unsolved problems in evolutionary biology, and although much progress had been made both via theory and empirical research, recent data suggest that sex chromosome evolution may be more complex than previously thought. The concept of sexual antagonism (when there is a positive intersexual genetic correlation in trait expression but opposite fitness effects of the trait(s) in males and females) has become essential to our understanding of sex chromosome evolution. The goal of this proposal is to understand how the interacting effects of sexual antagonism, sex-linked genetic variation, and sex-specific selection shape the genetic architecture of complex traits. I will test the hypotheses that: 1) individual sexually antagonistic loci are common in the genome, both in separate-sexed species and in hermaphrodites, and drive patterns of sexual antagonism often seen on the trait level. 2) That the response to sex-specific selection in sex-linked loci is usually due to standing sexually antagonistic genetic variation. 3) That sexually antagonistic variation is primarily non-additive in nature. To accomplish this, I will use a combination of approaches, including sex-limited experimental evolution of the X chromosome and reciprocal sex chromosome introgression among distantly related populations of Drosophila, quantitative genetic analysis and experimental evolution mimicking the creation of a novel sex chromosome in the hermaphroditic flatworm Macrostomum, and analytical and simulation modeling. This project will serve to confirm or refute the assumption that trait-level sexual antagonism reflects the contributions of many individual sexually antagonistic loci, increase our understanding of the contribution of coevolution of the sex chromosomes to population divergence, and help provide us with a better general understanding of how genotype maps to phenotype.
Summary
The origin and evolution of sexual reproduction and sex differences represents one of the major unsolved problems in evolutionary biology, and although much progress had been made both via theory and empirical research, recent data suggest that sex chromosome evolution may be more complex than previously thought. The concept of sexual antagonism (when there is a positive intersexual genetic correlation in trait expression but opposite fitness effects of the trait(s) in males and females) has become essential to our understanding of sex chromosome evolution. The goal of this proposal is to understand how the interacting effects of sexual antagonism, sex-linked genetic variation, and sex-specific selection shape the genetic architecture of complex traits. I will test the hypotheses that: 1) individual sexually antagonistic loci are common in the genome, both in separate-sexed species and in hermaphrodites, and drive patterns of sexual antagonism often seen on the trait level. 2) That the response to sex-specific selection in sex-linked loci is usually due to standing sexually antagonistic genetic variation. 3) That sexually antagonistic variation is primarily non-additive in nature. To accomplish this, I will use a combination of approaches, including sex-limited experimental evolution of the X chromosome and reciprocal sex chromosome introgression among distantly related populations of Drosophila, quantitative genetic analysis and experimental evolution mimicking the creation of a novel sex chromosome in the hermaphroditic flatworm Macrostomum, and analytical and simulation modeling. This project will serve to confirm or refute the assumption that trait-level sexual antagonism reflects the contributions of many individual sexually antagonistic loci, increase our understanding of the contribution of coevolution of the sex chromosomes to population divergence, and help provide us with a better general understanding of how genotype maps to phenotype.
Max ERC Funding
1 492 011 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym CONPOL
Project Contexts, networks and participation: The social logic of political engagement
Researcher (PI) Sven Aron Oskarsson
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Consolidator Grant (CoG), SH2, ERC-2015-CoG
Summary The statement that individuals’ immediate social circumstances influence how they think and act in the political sphere is a truism. However, both theoretical and empirical considerations have often prevented political scientists from incorporating this logic into analyses of political behavior. In the CONPOL project we argue that it is necessary to return to the idea that politics follows a social logic in order to push the theoretical and empirical boundaries in explaining political behavior. That is, people do not act as isolated individuals when confronting complex political tasks such as deciding whether to vote and which party or candidate to vote for. Instead politics should be seen as a social experience in which individuals arrive at their decisions within particular social settings: the family, the peer group, the workplace, the neighborhood. In what way do parents and other family members influence an individual’s political choices? What is the role of workmates and neighbors when individuals arrive at political decisions? Do friends and friends’ friends affect how you think and act in the political sphere? To answer such questions the standard approach to gather empirical evidence on political behavior based on national sample surveys needs to be complemented by the use of population wide register data. The empirical core of the CONPOL project is unique Swedish register data. Via the population registers provided by Statistics Sweden it is possible to identify several relevant social settings such as parent-child relations and the location of individuals within workplaces and neighborhoods. The registers also allow us to identify certain network links between individuals. Furthermore, Statistics Sweden holds information on several variables measuring important political traits. A major aim for CONPOL is to complement this information by scanning in and digitalizing election rolls with individual-level information on turnout across several elections.
Summary
The statement that individuals’ immediate social circumstances influence how they think and act in the political sphere is a truism. However, both theoretical and empirical considerations have often prevented political scientists from incorporating this logic into analyses of political behavior. In the CONPOL project we argue that it is necessary to return to the idea that politics follows a social logic in order to push the theoretical and empirical boundaries in explaining political behavior. That is, people do not act as isolated individuals when confronting complex political tasks such as deciding whether to vote and which party or candidate to vote for. Instead politics should be seen as a social experience in which individuals arrive at their decisions within particular social settings: the family, the peer group, the workplace, the neighborhood. In what way do parents and other family members influence an individual’s political choices? What is the role of workmates and neighbors when individuals arrive at political decisions? Do friends and friends’ friends affect how you think and act in the political sphere? To answer such questions the standard approach to gather empirical evidence on political behavior based on national sample surveys needs to be complemented by the use of population wide register data. The empirical core of the CONPOL project is unique Swedish register data. Via the population registers provided by Statistics Sweden it is possible to identify several relevant social settings such as parent-child relations and the location of individuals within workplaces and neighborhoods. The registers also allow us to identify certain network links between individuals. Furthermore, Statistics Sweden holds information on several variables measuring important political traits. A major aim for CONPOL is to complement this information by scanning in and digitalizing election rolls with individual-level information on turnout across several elections.
Max ERC Funding
1 621 940 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym DELMIT
Project Maintaining the Human Mitochondrial Genome
Researcher (PI) Maria Falkenberg Gustafsson
Host Institution (HI) GOETEBORGS UNIVERSITET
Call Details Consolidator Grant (CoG), LS1, ERC-2015-CoG
Summary Mitochondria are required to convert food into usable energy forms and every cell contains thousands of them. Unlike most other cellular compartments, mitochondria have their own genomes (mtDNA) that encode for 13 of the about 90 proteins present in the respiratory chain. All proteins necessary for mtDNA replication, as well as transcription and translation of mtDNA-encoded genes, are encoded in the nucleus. Mutations in nuclear-encoded proteins required for mtDNA maintenance is an important cause of neurodegeneration and muscle diseases. The common result of these defects is either mtDNA depletion or accumulation of multiple deletions of mtDNA in postmitotic tissues.
The long-term goal (or vision) of research in my laboratory is to understand in molecular detail how mtDNA is replicated and how this process is regulated in mammalian cells. To this end we use a protein biochemistry approach, which we combine with in vivo verification in cell lines. My group was in 2004 the first to reconstitute mtDNA replication in vitro and we have continued to develop even more elaborate system ever since. In the current application, the major focus is studies of the mitochondrial D-loop region, a triple-stranded structure in the mitochondrial genome. The D-loop functions as a regulatory hub and we will determine how initiation and termination of mtDNA replication is controlled from this region. We will also determine the physical organization of the mtDNA replication machinery at the replication fork and establish how mtDNA deletions, a classical hallmark of human ageing, are formed.
Summary
Mitochondria are required to convert food into usable energy forms and every cell contains thousands of them. Unlike most other cellular compartments, mitochondria have their own genomes (mtDNA) that encode for 13 of the about 90 proteins present in the respiratory chain. All proteins necessary for mtDNA replication, as well as transcription and translation of mtDNA-encoded genes, are encoded in the nucleus. Mutations in nuclear-encoded proteins required for mtDNA maintenance is an important cause of neurodegeneration and muscle diseases. The common result of these defects is either mtDNA depletion or accumulation of multiple deletions of mtDNA in postmitotic tissues.
The long-term goal (or vision) of research in my laboratory is to understand in molecular detail how mtDNA is replicated and how this process is regulated in mammalian cells. To this end we use a protein biochemistry approach, which we combine with in vivo verification in cell lines. My group was in 2004 the first to reconstitute mtDNA replication in vitro and we have continued to develop even more elaborate system ever since. In the current application, the major focus is studies of the mitochondrial D-loop region, a triple-stranded structure in the mitochondrial genome. The D-loop functions as a regulatory hub and we will determine how initiation and termination of mtDNA replication is controlled from this region. We will also determine the physical organization of the mtDNA replication machinery at the replication fork and establish how mtDNA deletions, a classical hallmark of human ageing, are formed.
Max ERC Funding
1 999 985 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
Project acronym DIALOY
Project Mosaic loss of chromosome Y (LOY) in blood cells - a new biomarker for risk of cancer and Alzheimer’s disease in men
Researcher (PI) Lars Anders Forsberg
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary My recent discoveries show that mosaic loss of chromosome Y (LOY) in peripheral blood is associated with increased risks of cancer and Alzheimer’s disease (AD). These conditions are responsible for >50% of morbidity/mortality in aging men. More than 15% of men older than 70 show some degree of LOY and these men survive on average only half as long as men without LOY. Smoking is strongly associated with LOY and remarkably, the fraction of cells with LOY decreases after cessation of smoking. Cells with LOY can be detected, and disease risks predicted, many years before clinical manifestation of disease. These results of associations between LOY, cancer and smoking have been published in Nature Genetics and Science during 2014.
The overall objective of the proposal is to develop LOY as a new, strong and predictive biomarker. To this end, the research program focuses on three objectives: 1) expanding the study of LOY and associations with disease risks in still larger cohorts; 2) investigating functional aspects of LOY; and 3) develop improved technology for LOY-detection. The successful execution of the project is essential before LOY-testing in clinics can be realized.
Diagnosis of cancer and AD in modern medicine is based on clinical symptoms of disease. Through earlier identification of individuals at increased risk for disease, preventive strategies could be applied, before the severe stages appear. Preliminary results affirm the feasibility of the project and provide proof-of-concept that LOY-tests can be used for early identification of men with increased risks for these diseases. In addition to improving diagnostics and therapeutics; implementation of LOY-testing could prevent smoking-related disease and reduce the health care costs. In the end, LOY-testing could decrease male mortality rates and possibly eliminate the sex-difference in life expectancy. The project will therefore benefit individual patients as well as healthcare systems and society at large.
Summary
My recent discoveries show that mosaic loss of chromosome Y (LOY) in peripheral blood is associated with increased risks of cancer and Alzheimer’s disease (AD). These conditions are responsible for >50% of morbidity/mortality in aging men. More than 15% of men older than 70 show some degree of LOY and these men survive on average only half as long as men without LOY. Smoking is strongly associated with LOY and remarkably, the fraction of cells with LOY decreases after cessation of smoking. Cells with LOY can be detected, and disease risks predicted, many years before clinical manifestation of disease. These results of associations between LOY, cancer and smoking have been published in Nature Genetics and Science during 2014.
The overall objective of the proposal is to develop LOY as a new, strong and predictive biomarker. To this end, the research program focuses on three objectives: 1) expanding the study of LOY and associations with disease risks in still larger cohorts; 2) investigating functional aspects of LOY; and 3) develop improved technology for LOY-detection. The successful execution of the project is essential before LOY-testing in clinics can be realized.
Diagnosis of cancer and AD in modern medicine is based on clinical symptoms of disease. Through earlier identification of individuals at increased risk for disease, preventive strategies could be applied, before the severe stages appear. Preliminary results affirm the feasibility of the project and provide proof-of-concept that LOY-tests can be used for early identification of men with increased risks for these diseases. In addition to improving diagnostics and therapeutics; implementation of LOY-testing could prevent smoking-related disease and reduce the health care costs. In the end, LOY-testing could decrease male mortality rates and possibly eliminate the sex-difference in life expectancy. The project will therefore benefit individual patients as well as healthcare systems and society at large.
Max ERC Funding
1 525 000 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym ECOSOCPOL
Project Social and Political Economics: Theory and Evidence
Researcher (PI) Torsten Persson
Host Institution (HI) STOCKHOLMS UNIVERSITET
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 EPIScOPE
Project Reversing the epigenetic state of oligodendrocyte precursors cells in multiple sclerosis
Researcher (PI) Gonçalo DE SÁ E SOUSA DE CASTELO BRANCO
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Consolidator Grant (CoG), LS7, ERC-2015-CoG
Summary Oligodendrocytes (OL) are glial cells that mediate myelination of neurons, a process that is defective in multiple sclerosis (MS). Although OL precursor cells (OPCs) can initially promote remyelination in MS, this regenerative mechanism eventually fails in progressive MS. OPCs go through several epigenetic states that ultimately define their potential to differentiate and myelinate. OPCs in progressive MS stall in a distinct epigenetic state, incompatible with differentiation and remyelination. We hypothesize that these OPCs regress to an epigenetic state reminiscent of the state of embryonic OPCs, which remain undifferentiated.
In this proposal, we aim to uncover the causes behind the remyelination failure upon disease progression in MS. We will determine the epigenetic/transcriptional states of OPCs during development and in MS, using single cell and bulk RNA sequencing and quantitative proteomics. We will further investigate how the interplay between transcription factors (TFs), chromatin modifiers (ChMs) and non-coding RNAs (ncRNAs) contributes to the transition between epigenetic states of OPCs. The results will allow the identification of ChMs and ncRNAs that can modulate these states and thereby control OPC differentiation and myelination. We will use this knowledge to investigate whether we can reverse the epigenetic state of OPCs in MS, in order to promote their differentiation and remyelination. The unique combination of leading-edge techniques such as SILAC coupled with immunoprecipitation and mass-spectrometry, single-cell RNA sequencing, ChIP-Sequencing, among others, will allow us to provide insights into novel epigenetic mechanisms that might be underlying the effects of environmental and lifestyle risk factors for MS. Moreover, this project has the potential to lead to the discovery of new targets for epigenetic-based therapies for MS, which could provide major opportunities for improved clinical outcome of MS patients in the near future.
Summary
Oligodendrocytes (OL) are glial cells that mediate myelination of neurons, a process that is defective in multiple sclerosis (MS). Although OL precursor cells (OPCs) can initially promote remyelination in MS, this regenerative mechanism eventually fails in progressive MS. OPCs go through several epigenetic states that ultimately define their potential to differentiate and myelinate. OPCs in progressive MS stall in a distinct epigenetic state, incompatible with differentiation and remyelination. We hypothesize that these OPCs regress to an epigenetic state reminiscent of the state of embryonic OPCs, which remain undifferentiated.
In this proposal, we aim to uncover the causes behind the remyelination failure upon disease progression in MS. We will determine the epigenetic/transcriptional states of OPCs during development and in MS, using single cell and bulk RNA sequencing and quantitative proteomics. We will further investigate how the interplay between transcription factors (TFs), chromatin modifiers (ChMs) and non-coding RNAs (ncRNAs) contributes to the transition between epigenetic states of OPCs. The results will allow the identification of ChMs and ncRNAs that can modulate these states and thereby control OPC differentiation and myelination. We will use this knowledge to investigate whether we can reverse the epigenetic state of OPCs in MS, in order to promote their differentiation and remyelination. The unique combination of leading-edge techniques such as SILAC coupled with immunoprecipitation and mass-spectrometry, single-cell RNA sequencing, ChIP-Sequencing, among others, will allow us to provide insights into novel epigenetic mechanisms that might be underlying the effects of environmental and lifestyle risk factors for MS. Moreover, this project has the potential to lead to the discovery of new targets for epigenetic-based therapies for MS, which could provide major opportunities for improved clinical outcome of MS patients in the near future.
Max ERC Funding
1 895 155 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym HeteroDynamic
Project Evolutionary Stability of Ubiquitous Root Symbiosis
Researcher (PI) Anna Rosling Larsson
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Starting Grant (StG), LS8, ERC-2015-STG
Summary Virtually all terrestrial plants depend on symbiotic interactions with fungi. Arbuscular mycorrhizal (AM) fungi evolved over 450 million years ago, are obligate biotrophs and cannot complete their lifecycle without obtaining carbon from host roots. Mediating nutrient uptake and sequestering carbon in soil this symbiosis lie at the core of all terrestrial ecosystems. Plants on the other hand are facultative mycotrophs but under natural conditions all host roots are colonized as a result of multiple beneficial effects of AM fungi. In the symbiosis, both plants and fungi are promiscuous, forming interactions across individuals and species. In the absence of host-symbiont specificity and given their inability to discriminate among partners prior to interaction, evolutionary theory predicts that “free riders” would evolve and spread. Yet AM fungi remain evolutionary and ecologically successful. I propose that this is thanks to their unique genomic organization, a temporally dynamic heterokaryosis.
Unlike other eukaryotes, AM fungi have no single nucleate stage in their life cycle, instead they reproduce asexually by forming large multinucleate spores. Genetic variation is high and nuclei can migrate and mix within extensive mycelial networks. My group has recently established a single nucleus genomics method to study genetic variation among nuclei within AM fungi. With this method I can resolve the extent of heterokaryosis in AM fungi and its temporal dynamics. I will study the emergence of “free riders” upon intra organismal segregation of genetically distinct nuclei during AM fungal adaptation to host. Further I will study how hyphal fusion and nuclear mixing counteract segregation to stabilize the symbiosis. The research program has great potential for novel discoveries of fundamental importance to evolutionary and environmental biology and will also contribute to agricultural practice and management of terrestrial ecosystems.
Summary
Virtually all terrestrial plants depend on symbiotic interactions with fungi. Arbuscular mycorrhizal (AM) fungi evolved over 450 million years ago, are obligate biotrophs and cannot complete their lifecycle without obtaining carbon from host roots. Mediating nutrient uptake and sequestering carbon in soil this symbiosis lie at the core of all terrestrial ecosystems. Plants on the other hand are facultative mycotrophs but under natural conditions all host roots are colonized as a result of multiple beneficial effects of AM fungi. In the symbiosis, both plants and fungi are promiscuous, forming interactions across individuals and species. In the absence of host-symbiont specificity and given their inability to discriminate among partners prior to interaction, evolutionary theory predicts that “free riders” would evolve and spread. Yet AM fungi remain evolutionary and ecologically successful. I propose that this is thanks to their unique genomic organization, a temporally dynamic heterokaryosis.
Unlike other eukaryotes, AM fungi have no single nucleate stage in their life cycle, instead they reproduce asexually by forming large multinucleate spores. Genetic variation is high and nuclei can migrate and mix within extensive mycelial networks. My group has recently established a single nucleus genomics method to study genetic variation among nuclei within AM fungi. With this method I can resolve the extent of heterokaryosis in AM fungi and its temporal dynamics. I will study the emergence of “free riders” upon intra organismal segregation of genetically distinct nuclei during AM fungal adaptation to host. Further I will study how hyphal fusion and nuclear mixing counteract segregation to stabilize the symbiosis. The research program has great potential for novel discoveries of fundamental importance to evolutionary and environmental biology and will also contribute to agricultural practice and management of terrestrial ecosystems.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym inHForm
Project Integrative omics of heart failure to inform discovery of novel drug targets and clinical biomarkers
Researcher (PI) J. Gustav Smith
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Heart failure is a leading cause of morbidity and mortality in the aging European populations. It is the end-stage of myocardial and valvular disease, arising from loss of viable or functional muscle cells in the heart. Therapy is complicated by the multitude of causes and comorbidities of heart failure. New therapeutic targets and clinical biomarkers to individually tailor therapy (‘precision medicine’) are greatly needed. This research program aims to realize the promise of precision medicine by applying an integrated proteomic, genomic and epidemiological approach to the underlying causes, mechanisms and consequences for heart failure. The program builds on unique Swedish nation-wide disease registers and large biobanks, the translational research profile of the investigator and experience in genomics, epidemiology and proteomics. The program includes five work packages: (1) comprehensive plasma protein profiling through a discovery pipeline including novel microarray-based methods and mass spectrometry in a population-based cohort of 6000 subjects and clinical cases to identify subjects at risk for heart disease (2) assessment of heritable components to outcomes in heart disease using nation-wide Swedish registers (3) genome-wide discovery of variants associated with risk of and outcomes in heart disease as well as endophenotypes for cardiac structure and function, using resequencing and DNA microarrays in large population-based cohorts including >70,000 subjects from three generations (4) expression profiling in human heart samples and a novel human cardiomyocyte strain assay to translate genomic and proteomic findings to understanding of pathophysiological mechanisms (5) evaluate the clinical importance of plasma proteins and genetic variants in >3000 clinical cases. This research program is anticipated to result in new insights into the pathophysiology of heart failure and discovery of drug targets and clinical biomarkers.
Summary
Heart failure is a leading cause of morbidity and mortality in the aging European populations. It is the end-stage of myocardial and valvular disease, arising from loss of viable or functional muscle cells in the heart. Therapy is complicated by the multitude of causes and comorbidities of heart failure. New therapeutic targets and clinical biomarkers to individually tailor therapy (‘precision medicine’) are greatly needed. This research program aims to realize the promise of precision medicine by applying an integrated proteomic, genomic and epidemiological approach to the underlying causes, mechanisms and consequences for heart failure. The program builds on unique Swedish nation-wide disease registers and large biobanks, the translational research profile of the investigator and experience in genomics, epidemiology and proteomics. The program includes five work packages: (1) comprehensive plasma protein profiling through a discovery pipeline including novel microarray-based methods and mass spectrometry in a population-based cohort of 6000 subjects and clinical cases to identify subjects at risk for heart disease (2) assessment of heritable components to outcomes in heart disease using nation-wide Swedish registers (3) genome-wide discovery of variants associated with risk of and outcomes in heart disease as well as endophenotypes for cardiac structure and function, using resequencing and DNA microarrays in large population-based cohorts including >70,000 subjects from three generations (4) expression profiling in human heart samples and a novel human cardiomyocyte strain assay to translate genomic and proteomic findings to understanding of pathophysiological mechanisms (5) evaluate the clinical importance of plasma proteins and genetic variants in >3000 clinical cases. This research program is anticipated to result in new insights into the pathophysiology of heart failure and discovery of drug targets and clinical biomarkers.
Max ERC Funding
1 496 625 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
