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 CAPTURE
Project CApturing Paradata for documenTing data creation and Use for the REsearch of the future
Researcher (PI) Isto HUVILA
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Consolidator Grant (CoG), SH3, ERC-2018-COG
Summary "Considerable investments have been made in Europe and worldwide in research data infrastructures. Instead of a general lack of data about data, it has become apparent that the pivotal factor that drastically constrains the use of data is the absence of contextual knowledge about how data was created and how it has been used. This applies especially to many branches of SSH research where data is highly heterogeneous, both by its kind (e.g. being qualitative, quantitative, naturalistic, purposefully created) and origins (e.g. being historical/contemporary, from different contexts and geographical places). The problem is that there may be enough metadata (data about data) but there is too little paradata (data on the processes of its creation and use).
In contrast to the rather straightforward problem of describing the data, the high-risk/high-gain problem no-one has managed to solve, is the lack of comprehensive understanding of what information about the creation and use of research data is needed and how to capture enough of that information to make the data reusable and to avoid the risk that currently collected vast amounts of research data become useless in the future. The wickedness of the problem lies in the practical impossibility to document and keep everything and the difficulty to determine optimal procedures for capturing just enough.
With an empirical focus on archaeological and cultural heritage data, which stands out by its extreme heterogeneity and rapid accumulation due to the scale of ongoing development-led archaeological fieldwork, CAPTURE develops an in-depth understanding of how paradata is #1 created and #2 used at the moment, #3 elicits methods for capturing paradata on the basis of the findings of #1-2, #4 tests the new methods in field trials, and #5 synthesises the findings in a reference model to inform the capturing of paradata and enabling data-intensive research using heterogeneous research data stemming from diverse origins.
"
Summary
"Considerable investments have been made in Europe and worldwide in research data infrastructures. Instead of a general lack of data about data, it has become apparent that the pivotal factor that drastically constrains the use of data is the absence of contextual knowledge about how data was created and how it has been used. This applies especially to many branches of SSH research where data is highly heterogeneous, both by its kind (e.g. being qualitative, quantitative, naturalistic, purposefully created) and origins (e.g. being historical/contemporary, from different contexts and geographical places). The problem is that there may be enough metadata (data about data) but there is too little paradata (data on the processes of its creation and use).
In contrast to the rather straightforward problem of describing the data, the high-risk/high-gain problem no-one has managed to solve, is the lack of comprehensive understanding of what information about the creation and use of research data is needed and how to capture enough of that information to make the data reusable and to avoid the risk that currently collected vast amounts of research data become useless in the future. The wickedness of the problem lies in the practical impossibility to document and keep everything and the difficulty to determine optimal procedures for capturing just enough.
With an empirical focus on archaeological and cultural heritage data, which stands out by its extreme heterogeneity and rapid accumulation due to the scale of ongoing development-led archaeological fieldwork, CAPTURE develops an in-depth understanding of how paradata is #1 created and #2 used at the moment, #3 elicits methods for capturing paradata on the basis of the findings of #1-2, #4 tests the new methods in field trials, and #5 synthesises the findings in a reference model to inform the capturing of paradata and enabling data-intensive research using heterogeneous research data stemming from diverse origins.
"
Max ERC Funding
1 944 162 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym CONPOL
Project Contexts, networks and participation: The social logic of political engagement
Researcher (PI) Sven Aron Oskarsson
Host Institution (HI) UPPSALA UNIVERSITET
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 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 DrivenByPollinators
Project Driven by mutualists: how declines in pollinators impact plant communities and ecosystemfunctioning
Researcher (PI) Yann Mats CLOUGH
Host Institution (HI) LUNDS UNIVERSITET
Country Sweden
Call Details Consolidator Grant (CoG), LS8, ERC-2018-COG
Summary Pollinator declines in response to land-use intensification have raised concern about the persistence of plant species dependent on insect pollination, in particular by bees, for their reproduction. Recent empirical studies show that reduced pollinator abundance decreases densities of seedlings of insect-pollinated plants and thereby changes the composition of grassland plant communities. Cascading effects on ecosystem functioning and associated organisms are expected, but to which extent and under which conditions this is the case is yet unexplored. Here, I propose a bold, multi-year, landscape-scale experimental assessment of the extent of pollinator-driven plant community changes, their consequences for associated organisms and important ecosystem functions, and their likely contingency on other factors (soil fertility, herbivory).
Specifically I will:
(1) Set up a network of long-term research plots in landscapes differing in pollinator abundance to measure the changes in plant reproduction over successive years, and assessing experimentally how herbivory and soil fertility mediate these effects.
(2) Explore the individual processes linking pollinators, plant communities and ecosystem functioning using long-term experiments controlling pollinator, herbivore and nutrient availability, focusing on a sample of plant species covering both the dominant species and a diversity of functional traits.
(3) Assess the context-dependence of pollinator-mediated plant community determination by building and applying process-based models based on observational and experimental data, and combine with existing spatially-explicit pollinator models to demonstrate the applicability to assess agri-environmental measures.
This powerful blend of complementary approaches will for the first time shed light on the cornerstone role of this major mutualism in maintaining diverse communities and the functions they support, and pinpoint the risks threatening them and the need for mitigation.
Summary
Pollinator declines in response to land-use intensification have raised concern about the persistence of plant species dependent on insect pollination, in particular by bees, for their reproduction. Recent empirical studies show that reduced pollinator abundance decreases densities of seedlings of insect-pollinated plants and thereby changes the composition of grassland plant communities. Cascading effects on ecosystem functioning and associated organisms are expected, but to which extent and under which conditions this is the case is yet unexplored. Here, I propose a bold, multi-year, landscape-scale experimental assessment of the extent of pollinator-driven plant community changes, their consequences for associated organisms and important ecosystem functions, and their likely contingency on other factors (soil fertility, herbivory).
Specifically I will:
(1) Set up a network of long-term research plots in landscapes differing in pollinator abundance to measure the changes in plant reproduction over successive years, and assessing experimentally how herbivory and soil fertility mediate these effects.
(2) Explore the individual processes linking pollinators, plant communities and ecosystem functioning using long-term experiments controlling pollinator, herbivore and nutrient availability, focusing on a sample of plant species covering both the dominant species and a diversity of functional traits.
(3) Assess the context-dependence of pollinator-mediated plant community determination by building and applying process-based models based on observational and experimental data, and combine with existing spatially-explicit pollinator models to demonstrate the applicability to assess agri-environmental measures.
This powerful blend of complementary approaches will for the first time shed light on the cornerstone role of this major mutualism in maintaining diverse communities and the functions they support, and pinpoint the risks threatening them and the need for mitigation.
Max ERC Funding
1 998 842 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
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
Project acronym FASDEM
Project Failing and Successful Sequences of Democratization
Researcher (PI) Staffan I. LINDBERG
Host Institution (HI) GOETEBORGS UNIVERSITET
Country Sweden
Call Details Consolidator Grant (CoG), SH2, ERC-2016-COG
Summary The study of democratization lies at the center of political science and is increasingly important in economics, sociology, and history, and has become a central foreign policy objective. Yet, there is little conclusive evidence about in particular endogenous sequences of democratization critical to our ability to provide sound policy advise. FASDEM promises to revolutionize our understanding of the trajectories that fail to lead to democracy, and the pathways that are successful, by addressing two key questions: Which are the failing versus successful sequences of democratization? What are the determining causal relationships in these sequences?
Critical is the just finalized Varieties of Democracy (V-Dem) dataset including some 350 indicators, 34 component-indices, and five main indices of varieties of democracy from 1900 to the present for 173countries – about 15 million data points on democracy. FASDEM, if funded, will use this data capitalizing on a set of novel analytical approaches, tools, and adaptations of modeling from evolutionary biology developed by a research team in a related, project, that together can establish sequences between sets of hundreds of ordinal variables. Under the second objective, FASDEM will take a step further developing upon the latest statistical methodologies of establishing causal identification in observational data, and use these to test each step of such manifest sequences. FASDEM will make a radical departure from the crude and “correlational” paradigm in democratization studies to detail and explain failing and successful sequences of democratization for the first time.
Summary
The study of democratization lies at the center of political science and is increasingly important in economics, sociology, and history, and has become a central foreign policy objective. Yet, there is little conclusive evidence about in particular endogenous sequences of democratization critical to our ability to provide sound policy advise. FASDEM promises to revolutionize our understanding of the trajectories that fail to lead to democracy, and the pathways that are successful, by addressing two key questions: Which are the failing versus successful sequences of democratization? What are the determining causal relationships in these sequences?
Critical is the just finalized Varieties of Democracy (V-Dem) dataset including some 350 indicators, 34 component-indices, and five main indices of varieties of democracy from 1900 to the present for 173countries – about 15 million data points on democracy. FASDEM, if funded, will use this data capitalizing on a set of novel analytical approaches, tools, and adaptations of modeling from evolutionary biology developed by a research team in a related, project, that together can establish sequences between sets of hundreds of ordinal variables. Under the second objective, FASDEM will take a step further developing upon the latest statistical methodologies of establishing causal identification in observational data, and use these to test each step of such manifest sequences. FASDEM will make a radical departure from the crude and “correlational” paradigm in democratization studies to detail and explain failing and successful sequences of democratization for the first time.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-03-01, End date: 2023-02-28
Project acronym HISTORICALDATABASE
Project The Swedish historical database project
Researcher (PI) Per Einar Pettersson Lidbom
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Consolidator Grant (CoG), SH1, ERC-2013-CoG
Summary The Swedish historical data base project will put together and make publicly available highly disaggregated data on roughly a yearly basis for about 2500 Swedish administrative districts over the period 1749-1952. The finished data set will consist of comprehensive and detailed information on economic activity, political characteristics, vital statistics, occupational structure, education, social and agriculture statistics and infrastructure investments (e.g., railway construction). The comprehensiveness and complete coverage of historical data at the local administrative level is what makes this project unique from an international perspective. Since Sweden has the longest continuous and reliable data series on population and vital statistics in the world,starting as early as 1749, makes it possible to construct a comprehensive panel data set over all 2,500 Swedish local administrative units covering a 200 year period. Consequently, the total number of observations for each variable can be as large as 0.5 million (N=2500×T=200). With this type of rich and disaggregated historical data it become possible to get a better understanding of economic growth, structural transformation and economic development. Also, within-country variation allows for more satisfying empirical identification strategies such as instrumental variables, regression discontinuities or difference-in-differences estimation. As a case in point, I have demonstrated the potential usefulness of the Swedish historical data by addressing the question of whether redistribution of resources towards the poor differs between types of democracy after democratization. The identification strategy is based on a regression-discontinuity design where the type of democracy partly is a function of population size. This paper is currently “revise and resubmit” 2nd round at Econometrica. After collecting the new data, we intend to studying a number of questions related to economic development and growth.
Summary
The Swedish historical data base project will put together and make publicly available highly disaggregated data on roughly a yearly basis for about 2500 Swedish administrative districts over the period 1749-1952. The finished data set will consist of comprehensive and detailed information on economic activity, political characteristics, vital statistics, occupational structure, education, social and agriculture statistics and infrastructure investments (e.g., railway construction). The comprehensiveness and complete coverage of historical data at the local administrative level is what makes this project unique from an international perspective. Since Sweden has the longest continuous and reliable data series on population and vital statistics in the world,starting as early as 1749, makes it possible to construct a comprehensive panel data set over all 2,500 Swedish local administrative units covering a 200 year period. Consequently, the total number of observations for each variable can be as large as 0.5 million (N=2500×T=200). With this type of rich and disaggregated historical data it become possible to get a better understanding of economic growth, structural transformation and economic development. Also, within-country variation allows for more satisfying empirical identification strategies such as instrumental variables, regression discontinuities or difference-in-differences estimation. As a case in point, I have demonstrated the potential usefulness of the Swedish historical data by addressing the question of whether redistribution of resources towards the poor differs between types of democracy after democratization. The identification strategy is based on a regression-discontinuity design where the type of democracy partly is a function of population size. This paper is currently “revise and resubmit” 2nd round at Econometrica. After collecting the new data, we intend to studying a number of questions related to economic development and growth.
Max ERC Funding
1 200 000 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym LEUKEMIABARRIER
Project The Leukemia-Initiating Cell: Genetic Determinants, Escape Mechanisms and Ontogenic Influence
Researcher (PI) David Bryder
Host Institution (HI) MAX IV Laboratory, Lund University
Country Sweden
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adults and strongly associated in incidence to advanced age. AML arises from immature hematopoietic progenitor cells via a sequential multistep process, but the nature of these steps remains to a large extent unknown. Therefore, while significant efforts have previously been invested in characterizing the molecular properties of late-stage AML, as diagnosed in patients, less information is available on the events that underlie leukemia initiation and progression. This includes the identity of potential mechanisms that restrict or eradicate developing leukemic cells; hurdles evaded at some point in time for AML to occur.
We have developed an inducible transgenic mouse model of AML that, when combined with high-resolution cell fractionation of primitive hematopoietic progenitor cells, offers a unique opportunity to track development of AML from the very first stages of cancer development. Using this, I propose to: 1) Identify and functionally validate molecular determinants that underlie why only some hematopoietic progenitor cells progress into AML, 2) To explore the extent and identity of immune surveillance/editing that accompany progression into AML, and 3) By building on my previous work on hematopoietic aging, to explore AML progression in the context of aging.
I anticipate the LEUKEMIABARRIER project to generate novel basic knowledge, not excluding with clinical relevance, with the potential to open up several new fields for further studies. This includes identification of novel cell-intrinsic regulators and immune responses, their underlying mechanisms, and their relationship to the increased incidence of AML with age.
Summary
Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adults and strongly associated in incidence to advanced age. AML arises from immature hematopoietic progenitor cells via a sequential multistep process, but the nature of these steps remains to a large extent unknown. Therefore, while significant efforts have previously been invested in characterizing the molecular properties of late-stage AML, as diagnosed in patients, less information is available on the events that underlie leukemia initiation and progression. This includes the identity of potential mechanisms that restrict or eradicate developing leukemic cells; hurdles evaded at some point in time for AML to occur.
We have developed an inducible transgenic mouse model of AML that, when combined with high-resolution cell fractionation of primitive hematopoietic progenitor cells, offers a unique opportunity to track development of AML from the very first stages of cancer development. Using this, I propose to: 1) Identify and functionally validate molecular determinants that underlie why only some hematopoietic progenitor cells progress into AML, 2) To explore the extent and identity of immune surveillance/editing that accompany progression into AML, and 3) By building on my previous work on hematopoietic aging, to explore AML progression in the context of aging.
I anticipate the LEUKEMIABARRIER project to generate novel basic knowledge, not excluding with clinical relevance, with the potential to open up several new fields for further studies. This includes identification of novel cell-intrinsic regulators and immune responses, their underlying mechanisms, and their relationship to the increased incidence of AML with age.
Max ERC Funding
1 999 714 €
Duration
Start date: 2014-07-01, End date: 2019-06-30
Project acronym LYMPHORG
Project Organ-specific mechanisms of lymphatic vascular development and specialisation
Researcher (PI) Taija Marianna Makinen
Host Institution (HI) UPPSALA UNIVERSITET
Country Sweden
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Lymphatic vasculature maintains tissue fluid homeostasis and has important emerging roles in inflammation, immunity, lipid metabolism, blood pressure regulation and cancer metastasis. Lymphatic vessels are specialised to fulfil the functional needs of different organs while diseases associated with lymphatic dysfunction frequently affect vessels of specific tissues. How functional specialisation of vessels is achieved and what underlies tissue-specific vessel failure is not understood. I hypothesise that organ-specific manifestation of lymphatic dysfunction in disease is due to vascular bed-specific differences in vessel formation. In this project my aim is to identify genes and mechanisms required for organ-specific lymphatic development. Building on our recent discovery of a previously unknown progenitor cell type that is required for lymphatic development in an organ-specific manner I set out to identify the origin and function of lymphatic endothelial progenitor cells (LEPC) during development and assess their potential for therapeutic lymphatic regeneration. Towards this aim, we will identify organ-specific origins of lymphatic vasculature using lineage tracing and determine genetic signatures of lymphatic endothelial progenitors by mRNA sequencing. Cells and tissues from normal and mutant mice that show organ-specific lymphatic defects will be analysed. To identify molecular and cellular mechanisms of LEPC derived vessel formation, we will functionally characterise LEPC signature genes using mouse models and visualise vessel development by in vivo two-photon microscopy. The function and therapeutic potential of LEPCs and LEPC derived vessels will be assessed using mouse models of tolerance, inflammation, obesity and lymphoedema. This work will provide novel insights into organ-specific mechanisms of vascular morphogenesis and identify a progenitor cell that may be expoited to restore lymphatic function in disorders associated with lymphatic vessel failure.
Summary
Lymphatic vasculature maintains tissue fluid homeostasis and has important emerging roles in inflammation, immunity, lipid metabolism, blood pressure regulation and cancer metastasis. Lymphatic vessels are specialised to fulfil the functional needs of different organs while diseases associated with lymphatic dysfunction frequently affect vessels of specific tissues. How functional specialisation of vessels is achieved and what underlies tissue-specific vessel failure is not understood. I hypothesise that organ-specific manifestation of lymphatic dysfunction in disease is due to vascular bed-specific differences in vessel formation. In this project my aim is to identify genes and mechanisms required for organ-specific lymphatic development. Building on our recent discovery of a previously unknown progenitor cell type that is required for lymphatic development in an organ-specific manner I set out to identify the origin and function of lymphatic endothelial progenitor cells (LEPC) during development and assess their potential for therapeutic lymphatic regeneration. Towards this aim, we will identify organ-specific origins of lymphatic vasculature using lineage tracing and determine genetic signatures of lymphatic endothelial progenitors by mRNA sequencing. Cells and tissues from normal and mutant mice that show organ-specific lymphatic defects will be analysed. To identify molecular and cellular mechanisms of LEPC derived vessel formation, we will functionally characterise LEPC signature genes using mouse models and visualise vessel development by in vivo two-photon microscopy. The function and therapeutic potential of LEPCs and LEPC derived vessels will be assessed using mouse models of tolerance, inflammation, obesity and lymphoedema. This work will provide novel insights into organ-specific mechanisms of vascular morphogenesis and identify a progenitor cell that may be expoited to restore lymphatic function in disorders associated with lymphatic vessel failure.
Max ERC Funding
2 368 439 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
