Project acronym Allelic Regulation
Project Revealing Allele-level Regulation and Dynamics using Single-cell Gene Expression Analyses
Researcher (PI) Thore Rickard Hakan Sandberg
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Consolidator Grant (CoG), LS2, ERC-2014-CoG
Summary As diploid organisms inherit one gene copy from each parent, a gene can be expressed from both alleles (biallelic) or from only one allele (monoallelic). Although transcription from both alleles is detected for most genes in cell population experiments, little is known about allele-specific expression in single cells and its phenotypic consequences. To answer fundamental questions about allelic transcription heterogeneity in single cells, this research program will focus on single-cell transcriptome analyses with allelic-origin resolution. To this end, we will investigate both clonally stable and dynamic random monoallelic expression across a large number of cell types, including cells from embryonic and adult stages. This research program will be accomplished with the novel single-cell RNA-seq method developed within my lab to obtain quantitative, genome-wide gene expression measurement. To distinguish between mitotically stable and dynamic patterns of allelic expression, we will analyze large numbers a clonally related cells per cell type, from both primary cultures (in vitro) and using transgenic models to obtain clonally related cells in vivo.
The biological significance of the research program is first an understanding of allelic transcription, including the nature and extent of random monoallelic expression across in vivo tissues and cell types. These novel insights into allelic transcription will be important for an improved understanding of how variable phenotypes (e.g. incomplete penetrance and variable expressivity) can arise in genetically identical individuals. Additionally, the single-cell transcriptome analyses of clonally related cells in vivo will provide unique insights into the clonality of gene expression per se.
Summary
As diploid organisms inherit one gene copy from each parent, a gene can be expressed from both alleles (biallelic) or from only one allele (monoallelic). Although transcription from both alleles is detected for most genes in cell population experiments, little is known about allele-specific expression in single cells and its phenotypic consequences. To answer fundamental questions about allelic transcription heterogeneity in single cells, this research program will focus on single-cell transcriptome analyses with allelic-origin resolution. To this end, we will investigate both clonally stable and dynamic random monoallelic expression across a large number of cell types, including cells from embryonic and adult stages. This research program will be accomplished with the novel single-cell RNA-seq method developed within my lab to obtain quantitative, genome-wide gene expression measurement. To distinguish between mitotically stable and dynamic patterns of allelic expression, we will analyze large numbers a clonally related cells per cell type, from both primary cultures (in vitro) and using transgenic models to obtain clonally related cells in vivo.
The biological significance of the research program is first an understanding of allelic transcription, including the nature and extent of random monoallelic expression across in vivo tissues and cell types. These novel insights into allelic transcription will be important for an improved understanding of how variable phenotypes (e.g. incomplete penetrance and variable expressivity) can arise in genetically identical individuals. Additionally, the single-cell transcriptome analyses of clonally related cells in vivo will provide unique insights into the clonality of gene expression per se.
Max ERC Funding
1 923 060 €
Duration
Start date: 2015-07-01, End date: 2020-12-31
Project acronym BIOMENDELIAN
Project Linking Cardiometabolic Disease and Cancer in the Level of Genetics, Circulating Biomarkers, Microbiota and Environmental Risk Factors
Researcher (PI) Marju Orho-Melander
Host Institution (HI) LUNDS UNIVERSITET
Country Sweden
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary Cardiovascular disease (CVD), type 2 diabetes (T2D) and obesity, collectively referred to as cardiometabolic disease, together with cancer are the major morbidities and causes of death. With few exceptions, research on cardiometabolic disease and cancer is funded, studied and clinically applied separately without fully taking advantage of knowledge on common pathways and treatment targets through interdisciplinary synergies. The purpose of this proposal is to reveal causal factors connecting and disconnecting cardiometabolic diseases and cancer, and to understand interactions between gut microbiota, host diet and genetic susceptibility in a comprehensive prospective cohort study design to subsequently allow design of intervention strategies to guide more personalized disease prevention.
1. We investigate causality between genetic risk factors for cardiometabolic disease associated traits and future incidence of T2D, CVD, cancer (total/breast/colon/prostate) and mortality (total, CVD- and cancer mortality), searching for causal factors in a prospective cohort with >15 y follow-up (N>30,000, incident cases N=3550, 4713, 5975, 6115 for T2D, CVD, cancer, mortality)
2. For the first time in a large population (N=6000), we investigate how gut and oral microbiome are regulated by dietary factors, gut satiety peptides and host genetics, and how such connections relate to cardiometabolic disease associated traits and cancer
3. We investigate the role of diet and gene-diet interactions of importance for cardiometabolic disease and cancer
4. We perform genotype, biomarker and gut microbiota based diet intervention studies.
This inter-disciplinary project contributes to biological understanding of basic disease mechanisms and takes steps towards better possibilities to prevent and treat individuals at high risk for cardiometabolic disease, cancer and death.
Summary
Cardiovascular disease (CVD), type 2 diabetes (T2D) and obesity, collectively referred to as cardiometabolic disease, together with cancer are the major morbidities and causes of death. With few exceptions, research on cardiometabolic disease and cancer is funded, studied and clinically applied separately without fully taking advantage of knowledge on common pathways and treatment targets through interdisciplinary synergies. The purpose of this proposal is to reveal causal factors connecting and disconnecting cardiometabolic diseases and cancer, and to understand interactions between gut microbiota, host diet and genetic susceptibility in a comprehensive prospective cohort study design to subsequently allow design of intervention strategies to guide more personalized disease prevention.
1. We investigate causality between genetic risk factors for cardiometabolic disease associated traits and future incidence of T2D, CVD, cancer (total/breast/colon/prostate) and mortality (total, CVD- and cancer mortality), searching for causal factors in a prospective cohort with >15 y follow-up (N>30,000, incident cases N=3550, 4713, 5975, 6115 for T2D, CVD, cancer, mortality)
2. For the first time in a large population (N=6000), we investigate how gut and oral microbiome are regulated by dietary factors, gut satiety peptides and host genetics, and how such connections relate to cardiometabolic disease associated traits and cancer
3. We investigate the role of diet and gene-diet interactions of importance for cardiometabolic disease and cancer
4. We perform genotype, biomarker and gut microbiota based diet intervention studies.
This inter-disciplinary project contributes to biological understanding of basic disease mechanisms and takes steps towards better possibilities to prevent and treat individuals at high risk for cardiometabolic disease, cancer and death.
Max ERC Funding
2 000 000 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym BOPNIE
Project Boundary value problems for nonlinear integrable equations
Researcher (PI) Jonatan Carl Anders Lenells
Host Institution (HI) KUNGLIGA TEKNISKA HOEGSKOLAN
Country Sweden
Call Details Consolidator Grant (CoG), PE1, ERC-2015-CoG
Summary The purpose of this project is to develop new methods for solving boundary value problems (BVPs) for nonlinear integrable partial differential equations (PDEs). Integrable PDEs can be analyzed by means of the Inverse Scattering Transform, whose introduction was one of the most important developments in the theory of nonlinear PDEs in the 20th century. Until the 1990s the inverse scattering methodology was pursued almost entirely for pure initial-value problems. However, in many laboratory and field situations, the solution is generated by what corresponds to the imposition of boundary conditions rather than initial conditions. Thus, an understanding of BVPs is crucial.
In an exciting sequence of events taking place in the last two decades, new tools have become available to deal with BVPs for integrable PDEs. Although some important issues have already been resolved, several major problems remain open.
The aim of this project is to solve a number of these open problems and to find solutions of BVPs which were heretofore not solvable. More precisely, the proposal has eight objectives:
1. Develop methods for solving problems with time-periodic boundary conditions.
2. Answer some long-standing open questions raised by series of wave-tank experiments 35 years ago.
3. Develop a new approach for the study of space-periodic solutions.
4. Develop new approaches for the analysis of BVPs for equations with 3 x 3-matrix Lax pairs.
5. Derive new asymptotic formulas by using a nonlinear version of the steepest descent method.
6. Construct disk and disk/black-hole solutions of the stationary axisymmetric Einstein equations.
7. Solve a BVP in Einstein's theory of relativity describing two colliding gravitational waves.
8. Extend the above methods to BVPs in higher dimensions.
Summary
The purpose of this project is to develop new methods for solving boundary value problems (BVPs) for nonlinear integrable partial differential equations (PDEs). Integrable PDEs can be analyzed by means of the Inverse Scattering Transform, whose introduction was one of the most important developments in the theory of nonlinear PDEs in the 20th century. Until the 1990s the inverse scattering methodology was pursued almost entirely for pure initial-value problems. However, in many laboratory and field situations, the solution is generated by what corresponds to the imposition of boundary conditions rather than initial conditions. Thus, an understanding of BVPs is crucial.
In an exciting sequence of events taking place in the last two decades, new tools have become available to deal with BVPs for integrable PDEs. Although some important issues have already been resolved, several major problems remain open.
The aim of this project is to solve a number of these open problems and to find solutions of BVPs which were heretofore not solvable. More precisely, the proposal has eight objectives:
1. Develop methods for solving problems with time-periodic boundary conditions.
2. Answer some long-standing open questions raised by series of wave-tank experiments 35 years ago.
3. Develop a new approach for the study of space-periodic solutions.
4. Develop new approaches for the analysis of BVPs for equations with 3 x 3-matrix Lax pairs.
5. Derive new asymptotic formulas by using a nonlinear version of the steepest descent method.
6. Construct disk and disk/black-hole solutions of the stationary axisymmetric Einstein equations.
7. Solve a BVP in Einstein's theory of relativity describing two colliding gravitational waves.
8. Extend the above methods to BVPs in higher dimensions.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-05-01, End date: 2022-02-28
Project acronym CellTrack
Project Cellular Position Tracking Using DNA Origami Barcodes
Researcher (PI) Bjoern HoeGBERG
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary The research I propose here will provide an enabling technology; spatially resolved transcriptomics, to address important problems in cell- and developmental-biology, in particular: How are stem cells in the skin and gut proliferating without turning into cancers? How are differentiated cells related, in their transcriptome and spatial positions, to their progenitors?
To investigate these problems on a molecular level and open up paths to find completely new spatiotemporal interdependencies in complex biological systems, I propose to use our newly developed DNA-origami strategy (Benson et al, Nature, 523 p. 441 (2015) ), combined with a combinatorial cloning technique, to build a new method for deep mRNA sequencing of tissue with single-cell resolution. These new types of origami are stable in physiological salt conditions and opens up their use in in-vivo applications.
In DNA-origami we can control the exact spatial position of all nucleotides. By folding the scaffold to display sequences for hybridization of fluorophores conjugated to DNA, we can create optical nano-barcodes. By using structures made out of DNA, the patterns of the optical barcodes will be readable both by imaging and by sequencing, thus enabling the creation of a mapping between cell locations in an organ and the mRNA expression of those cells.
We will use the method to perform spatially resolved transcriptomics in small organs: the mouse hair follicle, and small intestine crypt, and also perform the procedure for multiple samples collected at different time points. This will enable a high-dimensional data analysis that most likely will expose previously unknown dependencies that would provide completely new knowledge about how these biological systems work. By studying these systems, we will uncover much more information on how stem cells contribute to regeneration, the issue of de-differentiation that is a common theme in these organs and the effect this might have on the origin of cancer.
Summary
The research I propose here will provide an enabling technology; spatially resolved transcriptomics, to address important problems in cell- and developmental-biology, in particular: How are stem cells in the skin and gut proliferating without turning into cancers? How are differentiated cells related, in their transcriptome and spatial positions, to their progenitors?
To investigate these problems on a molecular level and open up paths to find completely new spatiotemporal interdependencies in complex biological systems, I propose to use our newly developed DNA-origami strategy (Benson et al, Nature, 523 p. 441 (2015) ), combined with a combinatorial cloning technique, to build a new method for deep mRNA sequencing of tissue with single-cell resolution. These new types of origami are stable in physiological salt conditions and opens up their use in in-vivo applications.
In DNA-origami we can control the exact spatial position of all nucleotides. By folding the scaffold to display sequences for hybridization of fluorophores conjugated to DNA, we can create optical nano-barcodes. By using structures made out of DNA, the patterns of the optical barcodes will be readable both by imaging and by sequencing, thus enabling the creation of a mapping between cell locations in an organ and the mRNA expression of those cells.
We will use the method to perform spatially resolved transcriptomics in small organs: the mouse hair follicle, and small intestine crypt, and also perform the procedure for multiple samples collected at different time points. This will enable a high-dimensional data analysis that most likely will expose previously unknown dependencies that would provide completely new knowledge about how these biological systems work. By studying these systems, we will uncover much more information on how stem cells contribute to regeneration, the issue of de-differentiation that is a common theme in these organs and the effect this might have on the origin of cancer.
Max ERC Funding
1 923 263 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym CONPOL
Project Contexts, networks and participation: The social logic of political engagement
Researcher (PI) Sven Aron Oskarsson
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
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
Country Sweden
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 DISLIFE
Project Liveable disabilities: Life courses and opportunity structures across time
Researcher (PI) Lotta Marie Christine Vikstroem
Host Institution (HI) UMEA UNIVERSITET
Country Sweden
Call Details Consolidator Grant (CoG), SH2, ERC-2014-CoG
Summary In Europe today disabled people comprise some 65 million (10%). Yet they are marginalized in society and research, and little is known on how disabilities become liveable. This project challenges this bias by proposing to investigate ‘liveable disabilities’ as a function of disability and opportunity structures across time. It analyses four life course dimensions: disabled people’s (1) health and well-being; (2) involvement in education and work; (3) in a partner relationship and family; and (4) in leisure structures. Through this I identify liveable disabilities before, during and after the Swedish welfare state. The results are of significant cross-national interest as they form a useful baseline for what constitutes liveable disabilities, which helps governing bodies maximize opportunity structures for disabled people to participate fully in society.
This proposal is unique in employing mixed-methods life course research across time. First, it involves quantitative analysis of Sweden’s long-term digitized population databases, which reflect how disability impacts on people’s educational, occupational, marital and survival chances. The statistical outcome is novel in demonstrating how different impairments intersect with human characteristics relative to society’s structures of the past 200 years. Second, qualitative analyses uncover how disabled people today experience and talk about the above dimensions (1-4) themselves, and how mass media depict them. Third, I make innovative studies of leisure structures, which may promote liveable disabilities.
The proposal aims to establish me at the forefront of disability research. It benefits from my scholarship in history and demography and from three excellent centres at Umeå University I am connected to, funded by the Swedish Research Council. One centre researches populations, another gender. The third provides expertise in disability studies and ready access to stakeholders outside academia.
Summary
In Europe today disabled people comprise some 65 million (10%). Yet they are marginalized in society and research, and little is known on how disabilities become liveable. This project challenges this bias by proposing to investigate ‘liveable disabilities’ as a function of disability and opportunity structures across time. It analyses four life course dimensions: disabled people’s (1) health and well-being; (2) involvement in education and work; (3) in a partner relationship and family; and (4) in leisure structures. Through this I identify liveable disabilities before, during and after the Swedish welfare state. The results are of significant cross-national interest as they form a useful baseline for what constitutes liveable disabilities, which helps governing bodies maximize opportunity structures for disabled people to participate fully in society.
This proposal is unique in employing mixed-methods life course research across time. First, it involves quantitative analysis of Sweden’s long-term digitized population databases, which reflect how disability impacts on people’s educational, occupational, marital and survival chances. The statistical outcome is novel in demonstrating how different impairments intersect with human characteristics relative to society’s structures of the past 200 years. Second, qualitative analyses uncover how disabled people today experience and talk about the above dimensions (1-4) themselves, and how mass media depict them. Third, I make innovative studies of leisure structures, which may promote liveable disabilities.
The proposal aims to establish me at the forefront of disability research. It benefits from my scholarship in history and demography and from three excellent centres at Umeå University I am connected to, funded by the Swedish Research Council. One centre researches populations, another gender. The third provides expertise in disability studies and ready access to stakeholders outside academia.
Max ERC Funding
1 999 870 €
Duration
Start date: 2016-02-01, End date: 2021-07-31
Project acronym ECOHERB
Project Drivers and impacts of invertebrate herbivores across forest ecosystems globally.
Researcher (PI) Daniel Metcalfe
Host Institution (HI) UMEA UNIVERSITET
Country Sweden
Call Details Consolidator Grant (CoG), PE10, ERC-2015-CoG
Summary Forests slow global climate change by absorbing atmospheric carbon dioxide but this ecosystem service is limited by soil nutrients. Herbivores potentially alter soil nutrients in a range of ways, but these have mostly only been recorded for large mammals. By comparison, the impacts of the abundant invertebrates in forests have largely been ignored and are not included in current models used to generate the climate predictions so vital for designing governmental policies
The proposed project will use a pioneering new interdisciplinary approach to provide the most complete picture yet available of the rates, underlying drivers and ultimate impacts of key nutrient inputs from invertebrate herbivores across forest ecosystems worldwide. Specifically, we will:
(1) Establish a network of herbivory monitoring stations across all major forest types, and across key environmental gradients (temperature, rainfall, ecosystem development).
(2) Perform laboratory experiments to examine the effects of herbivore excreta on soil processes under different temperature and moisture conditions.
(3) Integrate this information into a cutting-edge ecosystem model, to generate more accurate predictions of forest carbon sequestration under future climate change.
The network established will form the foundation for a unique long-term global monitoring effort which we intend to continue long after the current funding time scale. This work represents a powerful blend of several disciplines harnessing an array of cutting edge tools to provide fundamentally novel insights into an area of direct and urgent importance for the society.
Summary
Forests slow global climate change by absorbing atmospheric carbon dioxide but this ecosystem service is limited by soil nutrients. Herbivores potentially alter soil nutrients in a range of ways, but these have mostly only been recorded for large mammals. By comparison, the impacts of the abundant invertebrates in forests have largely been ignored and are not included in current models used to generate the climate predictions so vital for designing governmental policies
The proposed project will use a pioneering new interdisciplinary approach to provide the most complete picture yet available of the rates, underlying drivers and ultimate impacts of key nutrient inputs from invertebrate herbivores across forest ecosystems worldwide. Specifically, we will:
(1) Establish a network of herbivory monitoring stations across all major forest types, and across key environmental gradients (temperature, rainfall, ecosystem development).
(2) Perform laboratory experiments to examine the effects of herbivore excreta on soil processes under different temperature and moisture conditions.
(3) Integrate this information into a cutting-edge ecosystem model, to generate more accurate predictions of forest carbon sequestration under future climate change.
The network established will form the foundation for a unique long-term global monitoring effort which we intend to continue long after the current funding time scale. This work represents a powerful blend of several disciplines harnessing an array of cutting edge tools to provide fundamentally novel insights into an area of direct and urgent importance for the society.
Max ERC Funding
1 750 000 €
Duration
Start date: 2016-03-01, End date: 2022-02-28
Project acronym EPIScOPE
Project Reversing the epigenetic state of oligodendrocyte precursors cells in multiple sclerosis
Researcher (PI) Goncalo DE Sa E SOUSA DE CASTELO BRANCO
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
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 EVILTONGUE
Project No Sword Bites So Fiercly as an Evil Tongue?Gossip Wrecks Reputation, but Enhances Cooperation
Researcher (PI) Karoly Takacs
Host Institution (HI) LINKOPINGS UNIVERSITET
Country Sweden
Call Details Consolidator Grant (CoG), SH2, ERC-2014-CoG
Summary Social norms in general, and norms of cooperation in particular, are the cement of all human societies. For the difficult problems of the maintenance and enforcement of social norms and of cooperation, humans have developed surprisingly complex solutions. Reputation mechanisms and gossip are certainly among the compound informal solutions.
According to common wisdom, gossip channels mainly negative and often fictitious information. If it is so, how can dishonest gossip and the resulting biased reputations legitimize social order and promote cooperation?
This is the main puzzle we tackle in the proposed project exploiting a wide scale of instruments. We use analytical modeling and agent-based simulation to derive hypotheses. We test simple hypotheses in small group experiments. We develop new methodological tools to appropriately analyze the triadic nature of gossip embedded in network flows of information. We utilize dynamic network datasets from primary and secondary school classes, and we gather qualitative and quantitative information from organizations to test conditional hypotheses about the role that gossip plays in reputation and cooperation in different developmental and social contexts of life. In addition, we apply new communication technologies currently under development to explore the hidden world of gossip and the dynamics of reputations in dormitories and organizations.
With the insights gained, we can overcome common stereotypes about gossip and highlight how gossip is related to credible reputational signals, cooperation, and social order. Expected results will help us to outline the conditions that can promote cooperativeness in work groups, and they will help to construct successful prevention strategies of social exclusion and other potentially harmful consequences of the evil tongue.
Summary
Social norms in general, and norms of cooperation in particular, are the cement of all human societies. For the difficult problems of the maintenance and enforcement of social norms and of cooperation, humans have developed surprisingly complex solutions. Reputation mechanisms and gossip are certainly among the compound informal solutions.
According to common wisdom, gossip channels mainly negative and often fictitious information. If it is so, how can dishonest gossip and the resulting biased reputations legitimize social order and promote cooperation?
This is the main puzzle we tackle in the proposed project exploiting a wide scale of instruments. We use analytical modeling and agent-based simulation to derive hypotheses. We test simple hypotheses in small group experiments. We develop new methodological tools to appropriately analyze the triadic nature of gossip embedded in network flows of information. We utilize dynamic network datasets from primary and secondary school classes, and we gather qualitative and quantitative information from organizations to test conditional hypotheses about the role that gossip plays in reputation and cooperation in different developmental and social contexts of life. In addition, we apply new communication technologies currently under development to explore the hidden world of gossip and the dynamics of reputations in dormitories and organizations.
With the insights gained, we can overcome common stereotypes about gossip and highlight how gossip is related to credible reputational signals, cooperation, and social order. Expected results will help us to outline the conditions that can promote cooperativeness in work groups, and they will help to construct successful prevention strategies of social exclusion and other potentially harmful consequences of the evil tongue.
Max ERC Funding
1 973 500 €
Duration
Start date: 2015-12-01, End date: 2020-11-30
