Project acronym BIOFINDER
Project New biomarkers for Alzheimer’s & Parkinson’s diseases - key tools for early diagnosis and drug development
Researcher (PI) Oskar Hansson
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary Alzheimer’s disease (AD) and Parkinson’s disease (PD) are common in elderly and the prevalence of these is increasing. AD and PD have distinct pathogenesis, which precede the overt clinical symptoms by 10-15 years, opening a window for early diagnosis and treatment. New disease-modifying therapies are likely to be most efficient if initiated before the patients exhibit overt symptoms, making biomarkers for early diagnosis crucial for future clinical trials. Validated biomarkers would speed up initiation of treatment, avoid unnecessary investigations, and reduce patient insecurity.
AIMS: (1) identify and validate accurate and cost-effective blood-based biomarkers for early identification of those at high risk to develop AD and PD, (2) develop algorithms using advanced imaging and cerebrospinal fluid biomarkers for earlier more accurate diagnoses, and (3) better understand the underlying pathology and early progression of AD and PD, aiming at finding new relevant drug targets.
We will assess well-characterized and clinically relevant populations of patients and healthy elderly. We will use population- and clinic-based cohorts and follow them prospectively for 4 year. Participants will undergo neurocognitive evaluation, provide blood and cerebrospinal fluid, and have brain imaging using advanced MRI protocols and a newly developed PET-tracer visualizing brain amyloid. Sample will be analyzed with quantitative mass spectrometry and high sensitivity immunoassays.
New biomarkers and brain imaging techniques will aid early diagnosis and facilitate the development of disease-modifying therapies, since treatment can start earlier in the disease process. New methods to quantify relevant drug targets, such as oligomers of β-amyloid and α-synuclein, will be vital when selecting drug candidates for large-scale clinical trials. By improving both diagnosis and therapies the social and economic burden of dementia might be reduced by expanding the period of healthy and active aging
Summary
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are common in elderly and the prevalence of these is increasing. AD and PD have distinct pathogenesis, which precede the overt clinical symptoms by 10-15 years, opening a window for early diagnosis and treatment. New disease-modifying therapies are likely to be most efficient if initiated before the patients exhibit overt symptoms, making biomarkers for early diagnosis crucial for future clinical trials. Validated biomarkers would speed up initiation of treatment, avoid unnecessary investigations, and reduce patient insecurity.
AIMS: (1) identify and validate accurate and cost-effective blood-based biomarkers for early identification of those at high risk to develop AD and PD, (2) develop algorithms using advanced imaging and cerebrospinal fluid biomarkers for earlier more accurate diagnoses, and (3) better understand the underlying pathology and early progression of AD and PD, aiming at finding new relevant drug targets.
We will assess well-characterized and clinically relevant populations of patients and healthy elderly. We will use population- and clinic-based cohorts and follow them prospectively for 4 year. Participants will undergo neurocognitive evaluation, provide blood and cerebrospinal fluid, and have brain imaging using advanced MRI protocols and a newly developed PET-tracer visualizing brain amyloid. Sample will be analyzed with quantitative mass spectrometry and high sensitivity immunoassays.
New biomarkers and brain imaging techniques will aid early diagnosis and facilitate the development of disease-modifying therapies, since treatment can start earlier in the disease process. New methods to quantify relevant drug targets, such as oligomers of β-amyloid and α-synuclein, will be vital when selecting drug candidates for large-scale clinical trials. By improving both diagnosis and therapies the social and economic burden of dementia might be reduced by expanding the period of healthy and active aging
Max ERC Funding
1 500 000 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
Project acronym BIOLOCHANICS
Project Localization in biomechanics and mechanobiology of aneurysms: Towards personalized medicine
Researcher (PI) Stéphane Henri Anatole Avril
Host Institution (HI) ASSOCIATION POUR LA RECHERCHE ET LE DEVELOPPEMENT DES METHODES ET PROCESSUS INDUSTRIELS
Call Details Consolidator Grant (CoG), PE8, ERC-2014-CoG
Summary Rupture of Aortic Aneurysms (AA), which kills more than 30 000 persons every year in Europe and the USA, is a complex phenomenon that occurs when the wall stress exceeds the local strength of the aorta due to degraded properties of the tissue. The state of the art in AA biomechanics and mechanobiology reveals that major scientific challenges still have to be addressed to permit patient-specific computational predictions of AA rupture and enable localized repair of the structure with targeted pharmacologic treatment. A first challenge relates to ensuring an objective prediction of localized mechanisms preceding rupture. A second challenge relates to modelling the patient-specific evolutions of material properties leading to the localized mechanisms preceding rupture. Addressing these challenges is the aim of the BIOLOCHANICS proposal. We will take into account internal length-scales controlling localization mechanisms preceding AA rupture by implementing an enriched, also named nonlocal, continuum damage theory in the computational models of AA biomechanics and mechanobiology. We will also develop very advanced experiments, based on full-field optical measurements, aimed at characterizing localization mechanisms occurring in aortic tissues and at identifying local distributions of material properties at different stages of AA progression. A first in vivo application will be performed on genetic and pharmacological models of mice and rat AA. Eventually, a retrospective clinical study involving more than 100 patients at the Saint-Etienne University hospital will permit calibrating estimations of AA rupture risk thanks to our novel approaches and infuse them into future clinical practice. Through the achievements of BIOLOCHANICS, nonlocal mechanics will be possibly extended to other soft tissues for applications in orthopaedics, oncology, sport biomechanics, interventional surgery, human safety, cell biology, etc.
Summary
Rupture of Aortic Aneurysms (AA), which kills more than 30 000 persons every year in Europe and the USA, is a complex phenomenon that occurs when the wall stress exceeds the local strength of the aorta due to degraded properties of the tissue. The state of the art in AA biomechanics and mechanobiology reveals that major scientific challenges still have to be addressed to permit patient-specific computational predictions of AA rupture and enable localized repair of the structure with targeted pharmacologic treatment. A first challenge relates to ensuring an objective prediction of localized mechanisms preceding rupture. A second challenge relates to modelling the patient-specific evolutions of material properties leading to the localized mechanisms preceding rupture. Addressing these challenges is the aim of the BIOLOCHANICS proposal. We will take into account internal length-scales controlling localization mechanisms preceding AA rupture by implementing an enriched, also named nonlocal, continuum damage theory in the computational models of AA biomechanics and mechanobiology. We will also develop very advanced experiments, based on full-field optical measurements, aimed at characterizing localization mechanisms occurring in aortic tissues and at identifying local distributions of material properties at different stages of AA progression. A first in vivo application will be performed on genetic and pharmacological models of mice and rat AA. Eventually, a retrospective clinical study involving more than 100 patients at the Saint-Etienne University hospital will permit calibrating estimations of AA rupture risk thanks to our novel approaches and infuse them into future clinical practice. Through the achievements of BIOLOCHANICS, nonlocal mechanics will be possibly extended to other soft tissues for applications in orthopaedics, oncology, sport biomechanics, interventional surgery, human safety, cell biology, etc.
Max ERC Funding
1 999 396 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym BioMatrix
Project Structural Biology of Exopolysaccharide Secretion in Bacterial Biofilms
Researcher (PI) Petya Violinova KRASTEVA
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS1, ERC-2017-STG
Summary Bacterial biofilm formation is a paramount developmental process in both Gram-positive and Gram-negative species and in many pathogens has been associated with processes of horizontal gene transfer, antibiotic resistance development and pathogen persistence. Bacterial biofilms are collaborative sessile macrocolonies embedded in complex extracellular matrix that secures both mechanical resistance and a medium for intercellular exchange.
Biogenesis platforms for the secretion of biofilm matrix components - many of which controlled directly or indirectly by the intracellular second messenger c-di-GMP - are important determinants for biofilm formation and bacterial disease, and therefore present compelling targets for the development of novel therapeutics. During my Ph.D. and post-doctoral work I studied the structure and function of c-di-GMP-sensing protein factors controling extracellular matrix production by DNA-binding at the transcription initiation level or by inside-out signalling mechanisms at the cell envelope, as well as membrane exporters involved directly in downstream matrix component secretion.
Here, I propose to apply my expertise in microbiology, protein science and structural biology to study the structure and function of exopolysaccharide secretion systems in Gram-negative species. Using Pseudomonas aeruginosa, Vibrio spp. and Escherichia coli as model organisms, my team will aim to reveal the global architecture and individual building components of several expolysaccharide-producing protein megacomplexes. We will combine X-ray crystallography, biophysical and biochemical assays, electron microscopy and in cellulo functional studies to provide a comprehensive view of extracellular matrix production that spans the different resolution levels and presents molecular blueprints for the development of novel anti-infectives. Over the last year I have laid the foundation of these studies and have demonstrated the overall feasibility of the project.
Summary
Bacterial biofilm formation is a paramount developmental process in both Gram-positive and Gram-negative species and in many pathogens has been associated with processes of horizontal gene transfer, antibiotic resistance development and pathogen persistence. Bacterial biofilms are collaborative sessile macrocolonies embedded in complex extracellular matrix that secures both mechanical resistance and a medium for intercellular exchange.
Biogenesis platforms for the secretion of biofilm matrix components - many of which controlled directly or indirectly by the intracellular second messenger c-di-GMP - are important determinants for biofilm formation and bacterial disease, and therefore present compelling targets for the development of novel therapeutics. During my Ph.D. and post-doctoral work I studied the structure and function of c-di-GMP-sensing protein factors controling extracellular matrix production by DNA-binding at the transcription initiation level or by inside-out signalling mechanisms at the cell envelope, as well as membrane exporters involved directly in downstream matrix component secretion.
Here, I propose to apply my expertise in microbiology, protein science and structural biology to study the structure and function of exopolysaccharide secretion systems in Gram-negative species. Using Pseudomonas aeruginosa, Vibrio spp. and Escherichia coli as model organisms, my team will aim to reveal the global architecture and individual building components of several expolysaccharide-producing protein megacomplexes. We will combine X-ray crystallography, biophysical and biochemical assays, electron microscopy and in cellulo functional studies to provide a comprehensive view of extracellular matrix production that spans the different resolution levels and presents molecular blueprints for the development of novel anti-infectives. Over the last year I have laid the foundation of these studies and have demonstrated the overall feasibility of the project.
Max ERC Funding
1 499 901 €
Duration
Start date: 2018-08-01, End date: 2023-07-31
Project acronym BIOMECAMORPH
Project The Biomechanics of Epithelial Cell and Tissue Morphogenesis
Researcher (PI) Thomas Marie Michel Lecuit
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS3, ERC-2012-ADG_20120314
Summary Tissue morphogenesis is a complex process that emerges from spatially controlled patterns of cell shape changes. Dedicated genetic programmes regulate cell behaviours, exemplified in animals by the specification of apical constriction in invaginating epithelial tissues, or the orientation of cell intercalation during tissue extension. This genetic control is constrained by physical properties of cells that dictate how they can modify their shape. A major challenge is to understand how biochemical pathways control subcellular mechanics in epithelia, such as how forces are produced by interactions between actin filaments and myosin motors, and how these forces are transmitted at cell junctions. The major objective of our project is to investigate the fundamental principles of epithelial mechanics and to understand how intercellular signals and mechanical coupling between cells coordinate individual behaviours at the tissue level.
We will study early Drosophila embryogenesis and combine quantitative cell biological studies of cell dynamics, biophysical characterization of cell mechanics and genetic control of cell signalling to answer the following questions: i) how are forces generated, in particular what underlies deformation and stabilization of cell shape by actomyosin networks, and pulsatile contractility; ii) how are forces transmitted at junctions, what are the feedback interactions between tension generation and transmission; iii) how are individual cell mechanics orchestrated at the tissue level to yield collective tissue morphogenesis?
We expect to encapsulate the information-based, cell biological and physical descriptions of morphogenesis in a single, coherent framework. The project should impact more broadly on morphogenesis in other organisms and shed light on the mechanisms underlying robustness and plasticity in epithelia.
Summary
Tissue morphogenesis is a complex process that emerges from spatially controlled patterns of cell shape changes. Dedicated genetic programmes regulate cell behaviours, exemplified in animals by the specification of apical constriction in invaginating epithelial tissues, or the orientation of cell intercalation during tissue extension. This genetic control is constrained by physical properties of cells that dictate how they can modify their shape. A major challenge is to understand how biochemical pathways control subcellular mechanics in epithelia, such as how forces are produced by interactions between actin filaments and myosin motors, and how these forces are transmitted at cell junctions. The major objective of our project is to investigate the fundamental principles of epithelial mechanics and to understand how intercellular signals and mechanical coupling between cells coordinate individual behaviours at the tissue level.
We will study early Drosophila embryogenesis and combine quantitative cell biological studies of cell dynamics, biophysical characterization of cell mechanics and genetic control of cell signalling to answer the following questions: i) how are forces generated, in particular what underlies deformation and stabilization of cell shape by actomyosin networks, and pulsatile contractility; ii) how are forces transmitted at junctions, what are the feedback interactions between tension generation and transmission; iii) how are individual cell mechanics orchestrated at the tissue level to yield collective tissue morphogenesis?
We expect to encapsulate the information-based, cell biological and physical descriptions of morphogenesis in a single, coherent framework. The project should impact more broadly on morphogenesis in other organisms and shed light on the mechanisms underlying robustness and plasticity in epithelia.
Max ERC Funding
2 473 313 €
Duration
Start date: 2013-05-01, End date: 2018-04-30
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
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 BIOMOTIV
Project Why do we do what we do? Biological, psychological and computational bases of motivation
Researcher (PI) Mathias Pessiglione
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary We are largely unaware of our own motives. Understanding our motives can be reduced to knowing how we form goals and these goals translate into behavior. Goals can be defined as pleasurable situations that we particularly value and that we intend to reach. Recent investigation in the emerging field of neuro-economics has put forward a neuronal network constituting a brain valuation system (BVS). We wish to build a more comprehensive account of motivational processes, investigating not only valuation and choice but also effort (how much energy we would spend to attain a goal). More specifically, our aims are to better describe 1) how the brain assigns values to various objects and actions, 2) how values depend on parameters such as reward magnitude, probability, delay and cost, 3) how values are affected by social contexts, 4) how values are modified through learning and 5) how values influence the brain systems (perceptual, cognitive and motor) that underpin behavioral performance. To these aims, we would combine three approaches: 1) human cognitive neuroscience, which is central as we ultimately wish to understand ourselves, as well as human pathological conditions where motivation is either deficient (apathy) or out of control (compulsion), 2) primate neurophysiology, which is essential to describe information processing at the single-unit level and to derive causality by observing behavioral consequences of brain manipulations, 3) computational modeling, which is mandatory to link quantitatively the different descriptions levels (single-unit recordings, local field potentials, regional BOLD signal, vegetative manifestations and motor outputs). A bayesian framework will be developed to infer from experimental measures the subjects prior beliefs and value functions. We believe that our team, bringing together three complementary perspectives on motivation within a clinical environment, would represent a unique education and research center in Europe.
Summary
We are largely unaware of our own motives. Understanding our motives can be reduced to knowing how we form goals and these goals translate into behavior. Goals can be defined as pleasurable situations that we particularly value and that we intend to reach. Recent investigation in the emerging field of neuro-economics has put forward a neuronal network constituting a brain valuation system (BVS). We wish to build a more comprehensive account of motivational processes, investigating not only valuation and choice but also effort (how much energy we would spend to attain a goal). More specifically, our aims are to better describe 1) how the brain assigns values to various objects and actions, 2) how values depend on parameters such as reward magnitude, probability, delay and cost, 3) how values are affected by social contexts, 4) how values are modified through learning and 5) how values influence the brain systems (perceptual, cognitive and motor) that underpin behavioral performance. To these aims, we would combine three approaches: 1) human cognitive neuroscience, which is central as we ultimately wish to understand ourselves, as well as human pathological conditions where motivation is either deficient (apathy) or out of control (compulsion), 2) primate neurophysiology, which is essential to describe information processing at the single-unit level and to derive causality by observing behavioral consequences of brain manipulations, 3) computational modeling, which is mandatory to link quantitatively the different descriptions levels (single-unit recordings, local field potentials, regional BOLD signal, vegetative manifestations and motor outputs). A bayesian framework will be developed to infer from experimental measures the subjects prior beliefs and value functions. We believe that our team, bringing together three complementary perspectives on motivation within a clinical environment, would represent a unique education and research center in Europe.
Max ERC Funding
1 346 000 €
Duration
Start date: 2011-03-01, End date: 2016-08-31
Project acronym BIOSTASES
Project BIOdiversity, STAbility and sustainability in Spatial Ecological and social-ecological Systems
Researcher (PI) Michel Loreau
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS8, ERC-2014-ADG
Summary Biodiversity loss is one of the greatest environmental challenges of our time. There is mounting evidence that biodiversity increases the stability of ecosystem functions and services, suggesting that it may be critical to the sustainability of ecosystems and human societies in the face of environmental changes. Classical ecological theory, however, has focused on measures of stability that cannot explain and predict these stabilizing effects, especially in spatial systems.
The goal of BIOSTASES is to develop a coherent body of new theory on the stability of ecosystems and coupled social–ecological systems and its relationships with biodiversity at multiple spatial scales that can better inform empirical research. BIOSTASES will reach this goal through four complementary objectives. First, it will propose a mathematical framework focused on temporal variability as an empirically relevant measure of stability, and use this framework to build robust early warning signals for critical transitions. Second, it will use dynamical metacommunity models to explore a wide range of novel questions related to ecosystem stability and diversity–stability relationships across scales. Third, it will study the stability of complex meta-ecosystems to provide new perspectives on the stability of food webs and on synergies and trade-offs between multiple ecosystem services across space. Fourth, it will develop novel theory to study the long-term dynamics and sustainability of coupled social–ecological systems.
BIOSTASES proposes an ambitious innovative research programme that will provide new perspectives on the stability and sustainability of ecological and coupled social–ecological systems in the face of environmental changes. It will contribute to bridging the gaps between theoretical and empirical ecology and between ecology and social sciences, and to developing new approaches in biodiversity conservation, landscape management, and sustainable development.
Summary
Biodiversity loss is one of the greatest environmental challenges of our time. There is mounting evidence that biodiversity increases the stability of ecosystem functions and services, suggesting that it may be critical to the sustainability of ecosystems and human societies in the face of environmental changes. Classical ecological theory, however, has focused on measures of stability that cannot explain and predict these stabilizing effects, especially in spatial systems.
The goal of BIOSTASES is to develop a coherent body of new theory on the stability of ecosystems and coupled social–ecological systems and its relationships with biodiversity at multiple spatial scales that can better inform empirical research. BIOSTASES will reach this goal through four complementary objectives. First, it will propose a mathematical framework focused on temporal variability as an empirically relevant measure of stability, and use this framework to build robust early warning signals for critical transitions. Second, it will use dynamical metacommunity models to explore a wide range of novel questions related to ecosystem stability and diversity–stability relationships across scales. Third, it will study the stability of complex meta-ecosystems to provide new perspectives on the stability of food webs and on synergies and trade-offs between multiple ecosystem services across space. Fourth, it will develop novel theory to study the long-term dynamics and sustainability of coupled social–ecological systems.
BIOSTASES proposes an ambitious innovative research programme that will provide new perspectives on the stability and sustainability of ecological and coupled social–ecological systems in the face of environmental changes. It will contribute to bridging the gaps between theoretical and empirical ecology and between ecology and social sciences, and to developing new approaches in biodiversity conservation, landscape management, and sustainable development.
Max ERC Funding
2 092 644 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym BIRTOACTION
Project From birth to action: regulation of gene expression through transcription complex biogenesis
Researcher (PI) Laszlo Tora
Host Institution (HI) CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE
Call Details Advanced Grant (AdG), LS1, ERC-2013-ADG
Summary "Transcriptional regulation of protein coding genes in eukaryotic cells requires a complex interplay of sequence-specific DNA-binding factors, co-activators, general transcription factors (GTFs), RNA polymerase II and the epigenetic status of target sequences. Nuclear transcription complexes function as large multiprotein assemblies and are often composed of functional modules. The regulated decision-making that exists in cells governing the assembly and the allocation of factors to different transcription complexes to regulate distinct gene expression pathways is not yet understood. To tackle this fundamental question, we will systematically analyse the regulated biogenesis of transcription complexes from their sites of translation in the cytoplasm, through their assembly intermediates and nuclear import, to their site of action in the nucleus. The project will have four main Aims to decipher the biogenesis of transcription complexes:
I) Investigate their co-translation-driven assembly
II) Determine their cytoplasmic intermediates and factors required for their assembly pathways
III) Uncover their nuclear import
IV) Understand at the single molecule level their nuclear assembly, dynamics and action at target genes
To carry out these aims we propose a combination of multidisciplinary and cutting edge approaches, out of which some of them will be high-risk taking, while others will utilize methods routinely run by the group. The project builds on several complementary expertise and knowledge either already existing in the group or that will be implemented during the project. At the end of the proposed project we will obtain novel results extensively describing the different steps of the regulatory mechanisms that control the assembly and the consequent gene regulatory function of transcription complexes. Thus, we anticipate that the results of our research will have a major impact on the field and will lead to a new paradigm for contemporary metazoan transcription."
Summary
"Transcriptional regulation of protein coding genes in eukaryotic cells requires a complex interplay of sequence-specific DNA-binding factors, co-activators, general transcription factors (GTFs), RNA polymerase II and the epigenetic status of target sequences. Nuclear transcription complexes function as large multiprotein assemblies and are often composed of functional modules. The regulated decision-making that exists in cells governing the assembly and the allocation of factors to different transcription complexes to regulate distinct gene expression pathways is not yet understood. To tackle this fundamental question, we will systematically analyse the regulated biogenesis of transcription complexes from their sites of translation in the cytoplasm, through their assembly intermediates and nuclear import, to their site of action in the nucleus. The project will have four main Aims to decipher the biogenesis of transcription complexes:
I) Investigate their co-translation-driven assembly
II) Determine their cytoplasmic intermediates and factors required for their assembly pathways
III) Uncover their nuclear import
IV) Understand at the single molecule level their nuclear assembly, dynamics and action at target genes
To carry out these aims we propose a combination of multidisciplinary and cutting edge approaches, out of which some of them will be high-risk taking, while others will utilize methods routinely run by the group. The project builds on several complementary expertise and knowledge either already existing in the group or that will be implemented during the project. At the end of the proposed project we will obtain novel results extensively describing the different steps of the regulatory mechanisms that control the assembly and the consequent gene regulatory function of transcription complexes. Thus, we anticipate that the results of our research will have a major impact on the field and will lead to a new paradigm for contemporary metazoan transcription."
Max ERC Funding
2 500 000 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym BloodVariome
Project Genetic variation exposes regulators of blood cell formation in vivo in humans
Researcher (PI) Björn Erik Ake NILSSON
Host Institution (HI) LUNDS UNIVERSITET
Call Details Consolidator Grant (CoG), LS7, ERC-2017-COG
Summary The human hematopoietic system is a paradigmatic, stem cell-maintained organ with enormous cell turnover. Hundreds of billions of new blood cells are produced each day. The process is tightly regulated, and susceptible to perturbation due to genetic variation.
In this project, we will explore an innovative, population-genetic approach to find regulators of blood cell formation. Unlike traditional studies on hematopoiesis in vitro or in animal models, we will exploit natural genetic variation to identify DNA sequence variants and genes that influence blood cell formation in vivo in humans. Instead of inserting artificial mutations in mice, we will read out ripples from the experiments that nature has performed during evolution.
Building on our previous work, unique population-based materials, mathematical modeling, and the latest genomics and genome editing techniques, we will:
1. Develop high-resolution association data and analysis methods to find DNA sequence variants influencing human hematopoiesis, including stem- and progenitor stages.
2. Identify sequence variants and genes influencing specific stages of adult and fetal/perinatal hematopoiesis.
3. Define the function, and disease associations, of identified variants and genes.
Led by the applicant, the project will involve researchers at Lund University, Royal Institute of Technology and deCODE Genetics, and will be carried out in strong environments. It has been preceded by significant preparatory work. It will provide a first detailed analysis of how genetic variation influences human hematopoiesis, potentially increasing our understanding, and abilities to control, diseases marked by abnormal blood cell formation (e.g., leukemia).
Summary
The human hematopoietic system is a paradigmatic, stem cell-maintained organ with enormous cell turnover. Hundreds of billions of new blood cells are produced each day. The process is tightly regulated, and susceptible to perturbation due to genetic variation.
In this project, we will explore an innovative, population-genetic approach to find regulators of blood cell formation. Unlike traditional studies on hematopoiesis in vitro or in animal models, we will exploit natural genetic variation to identify DNA sequence variants and genes that influence blood cell formation in vivo in humans. Instead of inserting artificial mutations in mice, we will read out ripples from the experiments that nature has performed during evolution.
Building on our previous work, unique population-based materials, mathematical modeling, and the latest genomics and genome editing techniques, we will:
1. Develop high-resolution association data and analysis methods to find DNA sequence variants influencing human hematopoiesis, including stem- and progenitor stages.
2. Identify sequence variants and genes influencing specific stages of adult and fetal/perinatal hematopoiesis.
3. Define the function, and disease associations, of identified variants and genes.
Led by the applicant, the project will involve researchers at Lund University, Royal Institute of Technology and deCODE Genetics, and will be carried out in strong environments. It has been preceded by significant preparatory work. It will provide a first detailed analysis of how genetic variation influences human hematopoiesis, potentially increasing our understanding, and abilities to control, diseases marked by abnormal blood cell formation (e.g., leukemia).
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym BODY-OWNERSHIP
Project Neural mechanisms of body ownership and the projection of ownership onto artificial bodies
Researcher (PI) H. Henrik Ehrsson
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS4, ERC-2007-StG
Summary How do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.
Summary
How do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.
Max ERC Funding
909 850 €
Duration
Start date: 2008-12-01, End date: 2013-11-30
