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 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 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 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 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 Epi4MS
Project Targeting the epigenome: towards a better understanding of disease pathogenesis and novel therapeutic strategies in Multiple Sclerosis
Researcher (PI) Maja JAGODIC
Host Institution (HI) KAROLINSKA INSTITUTET
Country Sweden
Call Details Consolidator Grant (CoG), LS7, ERC-2018-COG
Summary Multiple Sclerosis (MS) is a leading cause of unpredictable and incurable progressive disability in young adults. Although the exact cause remains unknown, this immune-mediated disease is likely triggered by environmental factors in genetically predisposed individuals. I propose that epigenetic mechanisms, which regulate gene expression without affecting the genetic code, mediate the processes that cause MS and that aberrant epigenetic states can be corrected, spearheading the development of alternative therapies. We will exploit the stable and reversible nature of epigenetic marks, in particular DNA methylation, to gain insights into the novel modifiable disease mechanisms by studying the target organ in a way that has not been possible before. This highly ambitious project comprises three synergistic facets formulated in specific aims to: (i) identify epigenetic states that characterize the pathogenesis of MS, (ii) prioritize functional epigenetic states using high-throughput epigenome-screens, and (iii) develop novel approaches for precision medicine based on correcting causal epigenetic states. Our unique MS biobank combined with cutting-edge methodologies to capture pathogenic cells and measure their functional states provides a rational starting point to identify MS targets. I will complement this approach with studies of the functional impact of MS targets using innovative in vitro screens, with the added value of unbiased discovery of robust regulators of specific MS pathways. Finally, my laboratory has extensive experience with animal models of MS and I will utilize these powerful systems to dissect molecular mechanisms of MS targets and test the therapeutic potential of targeted epigenome editing in vivo. Our findings will set the stage for a paradigm-shift in studying and treating chronic inflammatory diseases based on preventing and modulating aggressive immune responses by inducing self-sustained reversal of aberrant epigenetic states.
Summary
Multiple Sclerosis (MS) is a leading cause of unpredictable and incurable progressive disability in young adults. Although the exact cause remains unknown, this immune-mediated disease is likely triggered by environmental factors in genetically predisposed individuals. I propose that epigenetic mechanisms, which regulate gene expression without affecting the genetic code, mediate the processes that cause MS and that aberrant epigenetic states can be corrected, spearheading the development of alternative therapies. We will exploit the stable and reversible nature of epigenetic marks, in particular DNA methylation, to gain insights into the novel modifiable disease mechanisms by studying the target organ in a way that has not been possible before. This highly ambitious project comprises three synergistic facets formulated in specific aims to: (i) identify epigenetic states that characterize the pathogenesis of MS, (ii) prioritize functional epigenetic states using high-throughput epigenome-screens, and (iii) develop novel approaches for precision medicine based on correcting causal epigenetic states. Our unique MS biobank combined with cutting-edge methodologies to capture pathogenic cells and measure their functional states provides a rational starting point to identify MS targets. I will complement this approach with studies of the functional impact of MS targets using innovative in vitro screens, with the added value of unbiased discovery of robust regulators of specific MS pathways. Finally, my laboratory has extensive experience with animal models of MS and I will utilize these powerful systems to dissect molecular mechanisms of MS targets and test the therapeutic potential of targeted epigenome editing in vivo. Our findings will set the stage for a paradigm-shift in studying and treating chronic inflammatory diseases based on preventing and modulating aggressive immune responses by inducing self-sustained reversal of aberrant epigenetic states.
Max ERC Funding
1 998 798 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
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 EXCHANGE
Project Dynamic Complexes and Allosteric Regulation of Small Molecule Transporters
Researcher (PI) David DREW
Host Institution (HI) STOCKHOLMS UNIVERSITET
Country Sweden
Call Details Consolidator Grant (CoG), LS1, ERC-2018-COG
Summary Solute Carrier (SLC) transporters mediate the translocation of substrates across membranes and after GPCRs represent the second-largest fraction of the human membrane proteome. SLC transporters are critical to cell homeostasis, which is reflected in the fact that more than a quarter is associated with Mendelian disease. Despite a few exceptions, however, they have been under-utilized as drug targets and most of the mechanistic understanding has been derived from bacterial homologues of these medically important proteins. In addition to subtle differences, bacterial homologues will not enable us to establish how the activities of many SLC transporters are allosterically regulated through the binding of accessory factors, e.g., hormones, to their non-membranous globular domains. Understanding the mechanisms by which their activities can be allosterically regulated through these complex and dynamic assembles is critical to human physiology and important for future drug design.
Our model system is a family of transporters known as sodium/proton exchangers (NHEs), which exchange sodium for protons across membranes to aid many fundamental processes in the cell. NHEs are important to the cell cycle, cell proliferation, cell migration and vesicle trafficking and are associated with a wide-spectrum of diseases. Their diverse portfolio is connected to the importance of pH homeostasis, and the binding of many different factors to a large, globular cytosolic domain exquisitely regulates them. To date, we have no structural information for any of the NHE’s, functional assays in liposomes are lacking, and many interaction partners are yet to be validated by in vitro studies. Determining the structure, dynamics, and allosteric regulation of NHEs will be an enormous challenge. However, we envisage that by achieving our objectives, we will reveal important mechanistic insights relevant not just to NHEs, but to many types of SLC transporters.
Summary
Solute Carrier (SLC) transporters mediate the translocation of substrates across membranes and after GPCRs represent the second-largest fraction of the human membrane proteome. SLC transporters are critical to cell homeostasis, which is reflected in the fact that more than a quarter is associated with Mendelian disease. Despite a few exceptions, however, they have been under-utilized as drug targets and most of the mechanistic understanding has been derived from bacterial homologues of these medically important proteins. In addition to subtle differences, bacterial homologues will not enable us to establish how the activities of many SLC transporters are allosterically regulated through the binding of accessory factors, e.g., hormones, to their non-membranous globular domains. Understanding the mechanisms by which their activities can be allosterically regulated through these complex and dynamic assembles is critical to human physiology and important for future drug design.
Our model system is a family of transporters known as sodium/proton exchangers (NHEs), which exchange sodium for protons across membranes to aid many fundamental processes in the cell. NHEs are important to the cell cycle, cell proliferation, cell migration and vesicle trafficking and are associated with a wide-spectrum of diseases. Their diverse portfolio is connected to the importance of pH homeostasis, and the binding of many different factors to a large, globular cytosolic domain exquisitely regulates them. To date, we have no structural information for any of the NHE’s, functional assays in liposomes are lacking, and many interaction partners are yet to be validated by in vitro studies. Determining the structure, dynamics, and allosteric regulation of NHEs will be an enormous challenge. However, we envisage that by achieving our objectives, we will reveal important mechanistic insights relevant not just to NHEs, but to many types of SLC transporters.
Max ERC Funding
1 999 875 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
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
