Project acronym 3D-REPAIR
Project Spatial organization of DNA repair within the nucleus
Researcher (PI) Evanthia Soutoglou
Host Institution (HI) THE UNIVERSITY OF SUSSEX
Country United Kingdom
Call Details Consolidator Grant (CoG), LS2, ERC-2015-CoG
Summary Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown.
Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps.
This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer
Summary
Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown.
Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps.
This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer
Max ERC Funding
1 999 750 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym BM
Project Becoming Muslim: Conversion to Islam and Islamisation in Eastern Ethiopia
Researcher (PI) Timothy Insoll
Host Institution (HI) THE UNIVERSITY OF EXETER
Country United Kingdom
Call Details Advanced Grant (AdG), SH6, ERC-2015-AdG
Summary "
Why do people convert to Islam? The contemporary relevance of this question is immediately apparent.""Becoming Muslim"" will transform our knowledge about Islamisation processes and contexts through archaeological research in Harar, Eastern Ethiopia, and examine this in comparison to other regions in sub-Saharan Africa via publication and a major conference. Assessing genuine belief is difficult, but the impact of trade, Saints, Sufis and Holy men, proselytisation, benefits gained from Arabic literacy and administration systems, enhanced power, prestige, warfare, and belonging to the larger Muslim community have all been suggested. Equally significant is the context of conversion. Why were certain sub-Saharan African cities key points for conversion to Islam, e.g. Gao and Timbuktu in the Western Sahel, and Harar in Ethiopia? Archaeological engagement with Islamisation processes and contexts of conversion in Africa is variable, and in parts of the continent research is static. This exciting 4-year project explores, for the first time, Islamic conversion and Islamisation through focusing on Harar, the most important living Islamic centre in the Horn of Africa, and its surrounding region.
Islamic archaeology has been neglected in Ethiopia, and is wholly non-existent in Harar. Excavation at 5 key sites: 2 shrines, 2 abandoned settlements, 1 urban site, will permit evaluation of urban Islam, the veneration of saints, pilgrimage and shrine based practices, rural Islam, architecture and jihad, changes in lifeways, and early and comparative evidence for Islam and long-distance trade, through analysis of, e.g. architecture, epigraphy, burial orientation, imported artifacts, and faunal and botanical remains. Although it is fully acknowledged that conversion to Islam and Islamisation processes are not universal, my project is groundbreaking in developing and applying a transferable methodology for the archaeological explanation of ""Becoming Muslim"" in sub-Saharan Africa."
Summary
"
Why do people convert to Islam? The contemporary relevance of this question is immediately apparent.""Becoming Muslim"" will transform our knowledge about Islamisation processes and contexts through archaeological research in Harar, Eastern Ethiopia, and examine this in comparison to other regions in sub-Saharan Africa via publication and a major conference. Assessing genuine belief is difficult, but the impact of trade, Saints, Sufis and Holy men, proselytisation, benefits gained from Arabic literacy and administration systems, enhanced power, prestige, warfare, and belonging to the larger Muslim community have all been suggested. Equally significant is the context of conversion. Why were certain sub-Saharan African cities key points for conversion to Islam, e.g. Gao and Timbuktu in the Western Sahel, and Harar in Ethiopia? Archaeological engagement with Islamisation processes and contexts of conversion in Africa is variable, and in parts of the continent research is static. This exciting 4-year project explores, for the first time, Islamic conversion and Islamisation through focusing on Harar, the most important living Islamic centre in the Horn of Africa, and its surrounding region.
Islamic archaeology has been neglected in Ethiopia, and is wholly non-existent in Harar. Excavation at 5 key sites: 2 shrines, 2 abandoned settlements, 1 urban site, will permit evaluation of urban Islam, the veneration of saints, pilgrimage and shrine based practices, rural Islam, architecture and jihad, changes in lifeways, and early and comparative evidence for Islam and long-distance trade, through analysis of, e.g. architecture, epigraphy, burial orientation, imported artifacts, and faunal and botanical remains. Although it is fully acknowledged that conversion to Islam and Islamisation processes are not universal, my project is groundbreaking in developing and applying a transferable methodology for the archaeological explanation of ""Becoming Muslim"" in sub-Saharan Africa."
Max ERC Funding
1 031 105 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym CAPRI
Project Children and Adolescents with PaRental mental Illness: Understanding the ‘who’ and ‘how’ of targeting interventions
Researcher (PI) Kathryn Mary Francis Abel
Host Institution (HI) THE UNIVERSITY OF MANCHESTER
Country United Kingdom
Call Details Consolidator Grant (CoG), LS7, ERC-2015-CoG
Summary At least 10% of mothers and 5% of fathers have a mental illness. Family, educational and social lives of children and adolescents with parental mental illness (CAPRI) are disrupted by deprivation and repeated hospitalisation. This is an urgent political and public health concern. The Child and Adolescent Mental Health in Europe (CAMHEE) report urges us ‘to acknowledge and attend to the needs of children and families with parental mental health.. ’ recommending better information on CAPRI risks and resilience so interventions can target those at highest risk. This groundbreaking interdisciplinary programme exploits my unique combination of expertise in epidemiology and neuroscience to deliver on CAMHEE objectives for CAPRI.
Previous work focuses on these ‘high risk’ children primarily to examine mental illness heritability. In a crucial departure from this, Work Packages (WP) 1 and 2 exploit my collaborations in Sweden and Australia to create unique linkage across 3 population datasets. This will detail CAPRI numbers and a broad range of life outcomes disentangling effects of social adversity over time. But population epidemiology alone cannot reveal how risk creates effects in individuals. To understand ‘how’ to identify ‘who’ we target for costly interventions, WP 3 links the epidemiology with powerful neuroimaging (near infrared spectroscopy NIRS) to discover which at-risk infants of mothers with severe mental illness show abnormal cognitive development at the level of individual brain.
This work capitalises on my role at the University of Manchester, one of the leading academic psychiatry and imaging centres in the UK, to create a new Centre in Bioepidemiology. My future aim is that epidemiological profiling combined with NIRS biomarkers of cognition in individuals will identify which high risk children need what intervention. Future work can then evaluate different interventions and fits seamlessly with my research goal to improve the life outcomes of CAPRI.
Summary
At least 10% of mothers and 5% of fathers have a mental illness. Family, educational and social lives of children and adolescents with parental mental illness (CAPRI) are disrupted by deprivation and repeated hospitalisation. This is an urgent political and public health concern. The Child and Adolescent Mental Health in Europe (CAMHEE) report urges us ‘to acknowledge and attend to the needs of children and families with parental mental health.. ’ recommending better information on CAPRI risks and resilience so interventions can target those at highest risk. This groundbreaking interdisciplinary programme exploits my unique combination of expertise in epidemiology and neuroscience to deliver on CAMHEE objectives for CAPRI.
Previous work focuses on these ‘high risk’ children primarily to examine mental illness heritability. In a crucial departure from this, Work Packages (WP) 1 and 2 exploit my collaborations in Sweden and Australia to create unique linkage across 3 population datasets. This will detail CAPRI numbers and a broad range of life outcomes disentangling effects of social adversity over time. But population epidemiology alone cannot reveal how risk creates effects in individuals. To understand ‘how’ to identify ‘who’ we target for costly interventions, WP 3 links the epidemiology with powerful neuroimaging (near infrared spectroscopy NIRS) to discover which at-risk infants of mothers with severe mental illness show abnormal cognitive development at the level of individual brain.
This work capitalises on my role at the University of Manchester, one of the leading academic psychiatry and imaging centres in the UK, to create a new Centre in Bioepidemiology. My future aim is that epidemiological profiling combined with NIRS biomarkers of cognition in individuals will identify which high risk children need what intervention. Future work can then evaluate different interventions and fits seamlessly with my research goal to improve the life outcomes of CAPRI.
Max ERC Funding
1 999 338 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym CIL2015
Project Dissecting the cellular mechanics of contact inhibition of locomotion
Researcher (PI) Brian Marc Stramer
Host Institution (HI) KING'S COLLEGE LONDON
Country United Kingdom
Call Details Consolidator Grant (CoG), LS3, ERC-2015-CoG
Summary Our aim is to dissect the mechanisms of contact inhibition of locomotion (CIL), a process whereby migrating cells collide and repel each other, as it is now clear that CIL is pivotal to understanding embryogenesis and pathologies such as cancer. We have developed an in vivo model using Drosophila macrophages (hemocytes), along with novel analytical tools, to examine the contact inhibition response in cells during development. We therefore have an unprecedented opportunity to address CIL in a genetically tractable organism within a physiologically relevant setting. This model has revealed that a precisely controlled CIL response is a significant driving force behind the acquisition of embryonic patterns, and recent data show that this precision requires a series of synchronized changes in cytoskeletal dynamics. Our central hypothesis is that key to this cellular ‘dance’ is mechanosensation of the collision, which integrates subsequent signaling mechanisms to choreograph the steps of the contact inhibition process. The first part of this proposal will elucidate the molecular mechanisms controlling CIL by exploiting our unique ability to live image and genetically dissect this process in Drosophila. We will also take an interdisciplinary approach to elucidate the mechanical aspects of the response, which will allow us to examine the feedback between signaling pathways and the physical forces of the CIL response. We will subsequently extend our detailed understanding of the CIL process, and our novel set of analytical tools, to mammalian cell types and model systems. This will allow us to develop new assays to directly probe the mechanics of CIL and begin to investigate the function of this underexplored process in other cell types. This in depth knowledge of the response places us in the best position to extend our understanding of CIL to new physiologically relevant scenarios that in the future will impact on human health.
Summary
Our aim is to dissect the mechanisms of contact inhibition of locomotion (CIL), a process whereby migrating cells collide and repel each other, as it is now clear that CIL is pivotal to understanding embryogenesis and pathologies such as cancer. We have developed an in vivo model using Drosophila macrophages (hemocytes), along with novel analytical tools, to examine the contact inhibition response in cells during development. We therefore have an unprecedented opportunity to address CIL in a genetically tractable organism within a physiologically relevant setting. This model has revealed that a precisely controlled CIL response is a significant driving force behind the acquisition of embryonic patterns, and recent data show that this precision requires a series of synchronized changes in cytoskeletal dynamics. Our central hypothesis is that key to this cellular ‘dance’ is mechanosensation of the collision, which integrates subsequent signaling mechanisms to choreograph the steps of the contact inhibition process. The first part of this proposal will elucidate the molecular mechanisms controlling CIL by exploiting our unique ability to live image and genetically dissect this process in Drosophila. We will also take an interdisciplinary approach to elucidate the mechanical aspects of the response, which will allow us to examine the feedback between signaling pathways and the physical forces of the CIL response. We will subsequently extend our detailed understanding of the CIL process, and our novel set of analytical tools, to mammalian cell types and model systems. This will allow us to develop new assays to directly probe the mechanics of CIL and begin to investigate the function of this underexplored process in other cell types. This in depth knowledge of the response places us in the best position to extend our understanding of CIL to new physiologically relevant scenarios that in the future will impact on human health.
Max ERC Funding
1 993 803 €
Duration
Start date: 2016-09-01, End date: 2022-08-31
Project acronym CLONCELLBREAST
Project CLONAL AND CELLULAR HETEROGENEITY OF BREAST CANCER AND ITS DYNAMIC EVOLUTION WITH TREATMENT
Researcher (PI) Carlos Manuel SIMAO DA SILVA CALDAS
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Advanced Grant (AdG), LS4, ERC-2015-AdG
Summary CLONAL AND CELLULAR HETEROGENEITY OF BREAST CANCER AND ITS DYNAMIC EVOLUTION WITH TREATMENT
Breast cancer remains one of the leading causes of cancer death in women. One of the greatest challenges is that breast cancer is a heterogeneous group of 10 diseases defined by genomic profiling. In addition, each tumor is composed of clones and clonal evolution underpins the successive acquisition of the hallmarks of cancer, including metastasis and resistance to therapy. Furthermore tumors display biologically and clinically relevant cellular heterogeneity: immune system, vasculature, and stroma. This cellular heterogeneity both shapes and is shaped by the malignant compartment and modulates response to therapy.
This proposal will use longitudinal studies to unravel the clonal and cellular heterogeneity of breast cancer and its dynamic evolution with treatment. The overall goal is to provide a systems level view of evolving clonal and cellular architectures in space and time along the clinical continuum of breast cancers in the clinic, leading to the discovery of new biological and clinical paradigms which will transform our understanding of the disease.
The overall approach is to capture the evolution of clonal and cellular heterogeneity of breast cancers in space and time using unique clinical cohorts where samples (biopsies and blood/plasma) are available spanning the whole disease continuum: early breast cancer surgically treated with curative intent, neo-adjuvant therapy, and matched relapse/metastasis. The 4 aims of the proposal are:
1. Characterization of the clonal and cellular heterogeneity of primary tumours from the 10 genomic driver-based breast cancer subtypes (ICs)
2. Comparative characterization of the clonal and cellular heterogeneity of matched pairs of primary and metastatic cancers
3. Characterization of the clonal and epigenetic evolution across therapy courses
4. Characterization of the immune response across therapy courses
Summary
CLONAL AND CELLULAR HETEROGENEITY OF BREAST CANCER AND ITS DYNAMIC EVOLUTION WITH TREATMENT
Breast cancer remains one of the leading causes of cancer death in women. One of the greatest challenges is that breast cancer is a heterogeneous group of 10 diseases defined by genomic profiling. In addition, each tumor is composed of clones and clonal evolution underpins the successive acquisition of the hallmarks of cancer, including metastasis and resistance to therapy. Furthermore tumors display biologically and clinically relevant cellular heterogeneity: immune system, vasculature, and stroma. This cellular heterogeneity both shapes and is shaped by the malignant compartment and modulates response to therapy.
This proposal will use longitudinal studies to unravel the clonal and cellular heterogeneity of breast cancer and its dynamic evolution with treatment. The overall goal is to provide a systems level view of evolving clonal and cellular architectures in space and time along the clinical continuum of breast cancers in the clinic, leading to the discovery of new biological and clinical paradigms which will transform our understanding of the disease.
The overall approach is to capture the evolution of clonal and cellular heterogeneity of breast cancers in space and time using unique clinical cohorts where samples (biopsies and blood/plasma) are available spanning the whole disease continuum: early breast cancer surgically treated with curative intent, neo-adjuvant therapy, and matched relapse/metastasis. The 4 aims of the proposal are:
1. Characterization of the clonal and cellular heterogeneity of primary tumours from the 10 genomic driver-based breast cancer subtypes (ICs)
2. Comparative characterization of the clonal and cellular heterogeneity of matched pairs of primary and metastatic cancers
3. Characterization of the clonal and epigenetic evolution across therapy courses
4. Characterization of the immune response across therapy courses
Max ERC Funding
2 497 660 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym ComparingCopperbelt
Project Comparing the Copperbelt: Political Culture and Knowledge Production in Central Africa
Researcher (PI) Miles Larmer
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Consolidator Grant (CoG), SH6, ERC-2015-CoG
Summary This project provides the first comparative historical analysis – local, national and transnational - of the Central African copperbelt. This globally strategic mineral region is central to the history of two nation-states (Zambia and Democratic Republic of Congo (DRC)), as well as wider debates about the role of mineral wealth in development. The project has three interrelated and comparative objectives. First, it will examine the copperbelt as a single region divided by a (post-)colonial border, across which flowed minerals, peoples, and ideas about the relationship between them. Political economy created the circumstances in which distinct political cultures of mining communities developed, but this also involved a process of imagination, drawing on ‘modern’ notions such as national development, but also morally framed ideas about the societies and land from which minerals are extracted. The project will explain the relationship between minerals and African polities, economies, societies and ideas. Second, it will analyse how ‘top-down’ knowledge production processes of Anglo-American and Belgian academies shaped understanding of these societies. Explaining how social scientists imagined and constructed copperbelt society will enable a new understanding of the relationship between mining societies and academic knowledge production. Third, it will explore the interaction between these intellectual constructions and the copperbelt’s political culture, exploring the interchange between academic and popular perceptions. This project will investigate the hypothesis that the resultant understanding of this region is the result of a long unequal interaction of definition and determination between western observers and African participants that has only a partial relationship to the reality of mineral extraction, filtered as it has been through successive sedimentations of imagining and representation laid down over nearly a century of urban life in central Africa.
Summary
This project provides the first comparative historical analysis – local, national and transnational - of the Central African copperbelt. This globally strategic mineral region is central to the history of two nation-states (Zambia and Democratic Republic of Congo (DRC)), as well as wider debates about the role of mineral wealth in development. The project has three interrelated and comparative objectives. First, it will examine the copperbelt as a single region divided by a (post-)colonial border, across which flowed minerals, peoples, and ideas about the relationship between them. Political economy created the circumstances in which distinct political cultures of mining communities developed, but this also involved a process of imagination, drawing on ‘modern’ notions such as national development, but also morally framed ideas about the societies and land from which minerals are extracted. The project will explain the relationship between minerals and African polities, economies, societies and ideas. Second, it will analyse how ‘top-down’ knowledge production processes of Anglo-American and Belgian academies shaped understanding of these societies. Explaining how social scientists imagined and constructed copperbelt society will enable a new understanding of the relationship between mining societies and academic knowledge production. Third, it will explore the interaction between these intellectual constructions and the copperbelt’s political culture, exploring the interchange between academic and popular perceptions. This project will investigate the hypothesis that the resultant understanding of this region is the result of a long unequal interaction of definition and determination between western observers and African participants that has only a partial relationship to the reality of mineral extraction, filtered as it has been through successive sedimentations of imagining and representation laid down over nearly a century of urban life in central Africa.
Max ERC Funding
1 599 661 €
Duration
Start date: 2016-07-01, End date: 2021-09-30
Project acronym COTCA
Project Cultures of Occupation in Twentieth-century Asia
Researcher (PI) Jeremy Edmund Taylor
Host Institution (HI) THE UNIVERSITY OF NOTTINGHAM
Country United Kingdom
Call Details Consolidator Grant (CoG), SH6, ERC-2015-CoG
Summary How has foreign occupation shaped culture? What has been the lasting cultural legacy of foreign occupation in those societies where it represented the usual state of affairs for much of the modern era? These are key questions which, in light of ongoing cases of occupation around the world, remain crucial in the 21st century. Cultures of Occupation in Twentieth-century Asia (COTCA) will answer these questions by analysing how occupation―be it under colonial, wartime or Cold War powers―gave rise to unique visual, auditory and spatial regimes in East and Southeast Asia. The core objective of this important project is to produce a paradigm shift in the study of occupation, and to challenge the 'collaboration'/'resistance' dichotomy which has defined the field thus far. It will adopt a transnational, intertextual and comparative approach to the study of cultural expression produced under occupation from the 1930s to the 1970s. It will also break new methodological ground by drawing on and contributing to recent developments in visual, auditory and spatial history as a means of highlighting intersections and cultural convergences across different types of occupation. By doing so, COTCA will, for the first time, determine what occupation looked, sounded and felt like in twentieth-century Asia. The COTCA team will consist of the PI, 2 postdoctoral researchers and 3 PhD students, and will run along 3 streams: (i) Representations of occupation; (ii) sounds of occupation; and (iii) spaces of occupation. Case studies based on hitherto rarely examined examples will be undertaken in each stream. These include: A visual history of Japanese-occupied China; soundscapes of the US naval bases in the Philippines; and, spaces of occupation in late-colonial Malaya. COTCA will also build a Digital Archive which will enable researchers to trace the development of narratives, tropes and motifs common to 'occupation' cultural expression in Asia across national and temporal borders.
Summary
How has foreign occupation shaped culture? What has been the lasting cultural legacy of foreign occupation in those societies where it represented the usual state of affairs for much of the modern era? These are key questions which, in light of ongoing cases of occupation around the world, remain crucial in the 21st century. Cultures of Occupation in Twentieth-century Asia (COTCA) will answer these questions by analysing how occupation―be it under colonial, wartime or Cold War powers―gave rise to unique visual, auditory and spatial regimes in East and Southeast Asia. The core objective of this important project is to produce a paradigm shift in the study of occupation, and to challenge the 'collaboration'/'resistance' dichotomy which has defined the field thus far. It will adopt a transnational, intertextual and comparative approach to the study of cultural expression produced under occupation from the 1930s to the 1970s. It will also break new methodological ground by drawing on and contributing to recent developments in visual, auditory and spatial history as a means of highlighting intersections and cultural convergences across different types of occupation. By doing so, COTCA will, for the first time, determine what occupation looked, sounded and felt like in twentieth-century Asia. The COTCA team will consist of the PI, 2 postdoctoral researchers and 3 PhD students, and will run along 3 streams: (i) Representations of occupation; (ii) sounds of occupation; and (iii) spaces of occupation. Case studies based on hitherto rarely examined examples will be undertaken in each stream. These include: A visual history of Japanese-occupied China; soundscapes of the US naval bases in the Philippines; and, spaces of occupation in late-colonial Malaya. COTCA will also build a Digital Archive which will enable researchers to trace the development of narratives, tropes and motifs common to 'occupation' cultural expression in Asia across national and temporal borders.
Max ERC Funding
1 885 268 €
Duration
Start date: 2016-07-01, End date: 2022-06-30
Project acronym EVALVE
Project Biomechanics and signaling in models of congenital heart valve defects
Researcher (PI) Julien Jean-Louis Marie Vermot
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Country United Kingdom
Call Details Consolidator Grant (CoG), LS4, ERC-2015-CoG
Summary Mechanical forces are fundamental to cardiovascular development and physiology. The interactions between mechanical forces and endothelial cells are mediated by mechanotransduction feedback loops. My lab is interested in understanding how hemodynamic forces modulate cardiovascular function and morphogenesis. Overall, our recent work is unraveling the biological links between mechanical forces, mechanotransduction and endothelial cell responses. The heart beats 2.6 billion times in a human lifetime and heart valves are amongst the most mechanically challenged structures of the body. The cardiac valves are made of endocardial cells (EdCs) and extracellular matrix components. Most valve diseases have their origins in embryogenesis, either as signs of abnormal developmental processes or the aberrant re-expression of fetal gene programs normally quiescent in adulthood.
This project is directed towards the elucidation of the biomechanical mechanism of mechanotransduction at the subcellular and molecular level and in addressing how EdCs integrate this information to form and maintain a functional cardiac valve. We will identify the mechanosensors at work in EdCs and their roles during cardiac valve development and repair. To do so, we will implement unique optical methodologies the lab has pioneered to characterize endocardial mechanotransduction: 1) Optical tweezing combined with mechanical stress reporters to test the mechanosensitivity of EdCs; 2) High resolution live microscopy and mathematical modeling to quantify mechanical forces; 3) 3D cell lineage studies to understand how cells respond and organize during pathological valve development. We will also use high-throughput mRNA- and ChIP-sequencing to characterize the transcriptional network activated by forces.
When completed this proposal will shed light on a critical, but little explored, aspect of congenital valve defects and will be useful for identifying new targets for therapeutic interventions.
Summary
Mechanical forces are fundamental to cardiovascular development and physiology. The interactions between mechanical forces and endothelial cells are mediated by mechanotransduction feedback loops. My lab is interested in understanding how hemodynamic forces modulate cardiovascular function and morphogenesis. Overall, our recent work is unraveling the biological links between mechanical forces, mechanotransduction and endothelial cell responses. The heart beats 2.6 billion times in a human lifetime and heart valves are amongst the most mechanically challenged structures of the body. The cardiac valves are made of endocardial cells (EdCs) and extracellular matrix components. Most valve diseases have their origins in embryogenesis, either as signs of abnormal developmental processes or the aberrant re-expression of fetal gene programs normally quiescent in adulthood.
This project is directed towards the elucidation of the biomechanical mechanism of mechanotransduction at the subcellular and molecular level and in addressing how EdCs integrate this information to form and maintain a functional cardiac valve. We will identify the mechanosensors at work in EdCs and their roles during cardiac valve development and repair. To do so, we will implement unique optical methodologies the lab has pioneered to characterize endocardial mechanotransduction: 1) Optical tweezing combined with mechanical stress reporters to test the mechanosensitivity of EdCs; 2) High resolution live microscopy and mathematical modeling to quantify mechanical forces; 3) 3D cell lineage studies to understand how cells respond and organize during pathological valve development. We will also use high-throughput mRNA- and ChIP-sequencing to characterize the transcriptional network activated by forces.
When completed this proposal will shed light on a critical, but little explored, aspect of congenital valve defects and will be useful for identifying new targets for therapeutic interventions.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-12-01, End date: 2023-05-31
Project acronym Gen-Epix
Project Genetic Determinants of the Epigenome
Researcher (PI) Adrian Peter BIRD
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Country United Kingdom
Call Details Advanced Grant (AdG), LS2, ERC-2015-AdG
Summary Decoding of the genome during development and differentiation depends on sequence-specific DNA binding proteins that regulate transcription. The activity of transcription factors is constrained, however, by chromatin structure and by modification of histones and DNA, known collectively as the “epigenome”. Diseased states, particularly cancers, are often accompanied by epigenomic disturbances that contribute to aetiology, but despite much research the molecular determinants of chromatin and DNA marking remain poorly understood. A widespread view is that the epigenome responds to developmental decisions or environmental impacts that are memorised by the epigenetic machinery. Complementary to this “memory” hypothesis, there is evidence that the epigenome can directly reflect the underlying DNA sequence. We aim to explore genetic determinants of the epigenome based on our over-arching hypothesis that chromatin structure is influenced by the interaction of DNA binding proteins with short, frequent base sequence motifs. Prototypes for this scenario are proteins that bind to the two base pair sequence CpG. These proteins accumulate at CpG islands (CGIs), which are platforms for gene regulation, where they recruit multi-protein complexes that lay down epigenetic marks. By identifying and characterising novel DNA-binding proteins that sense global properties of the DNA sequence (e.g. base composition), we will address several major unanswered questions about genome regulation, including the origin of global DNA methylation patterns and the causal basis of higher order chromosome structures. Our research programme will advance genome biology and shed light on the role of epigenetic signalling in development. In particular it will explore the extent to which the epigenome is “hard-wired” by genes, with important implications for health.
Summary
Decoding of the genome during development and differentiation depends on sequence-specific DNA binding proteins that regulate transcription. The activity of transcription factors is constrained, however, by chromatin structure and by modification of histones and DNA, known collectively as the “epigenome”. Diseased states, particularly cancers, are often accompanied by epigenomic disturbances that contribute to aetiology, but despite much research the molecular determinants of chromatin and DNA marking remain poorly understood. A widespread view is that the epigenome responds to developmental decisions or environmental impacts that are memorised by the epigenetic machinery. Complementary to this “memory” hypothesis, there is evidence that the epigenome can directly reflect the underlying DNA sequence. We aim to explore genetic determinants of the epigenome based on our over-arching hypothesis that chromatin structure is influenced by the interaction of DNA binding proteins with short, frequent base sequence motifs. Prototypes for this scenario are proteins that bind to the two base pair sequence CpG. These proteins accumulate at CpG islands (CGIs), which are platforms for gene regulation, where they recruit multi-protein complexes that lay down epigenetic marks. By identifying and characterising novel DNA-binding proteins that sense global properties of the DNA sequence (e.g. base composition), we will address several major unanswered questions about genome regulation, including the origin of global DNA methylation patterns and the causal basis of higher order chromosome structures. Our research programme will advance genome biology and shed light on the role of epigenetic signalling in development. In particular it will explore the extent to which the epigenome is “hard-wired” by genes, with important implications for health.
Max ERC Funding
2 499 717 €
Duration
Start date: 2016-06-01, End date: 2021-12-31
Project acronym IdrSeq
Project Discovery and characterization of functional disordered regions and the genes involved in their regulation through next generation sequencing
Researcher (PI) Madanbabu Mohan
Host Institution (HI) UNITED KINGDOM RESEARCH AND INNOVATION
Country United Kingdom
Call Details Consolidator Grant (CoG), LS2, ERC-2015-CoG
Summary A large fraction of any eukaryotic genome (>40%) encodes protein segments that do not adopt a defined tertiary structure. These proteins or regions are called intrinsically disordered proteins/regions (IDPs/IDRs). IDRs are enriched in critical functions such as transcription and signaling, and have been linked with numerous diseases including neurodegeneration and cancer. In contrast to structured regions, the molecular principles behind the sequence-function relationship of IDRs remain poorly understood.
We propose to identify functional IDRs and discover genes that regulate their function using yeast as a cellular model. We will develop and apply a targeted, high-throughput approach called IdrSeq. This technology exploits next generation sequencing to simultaneously assay vast libraries of sequences (~millions) that code for IDRs by coupling IDR sequence (genotype) to a selectable function (phenotype) and identifying functional variants through a selection experiment.
Specifically, using IdrSeq, we aim to identify and characterize IDRs in a cellular context that can
(Aim 1) activate transcription, and discover genes that regulate IDR mediated transcription
(Aim 2) influence protein stability, and discover genes that regulate IDR mediated half-life
(Aim 3) form higher-order assemblies and discover genes that regulate assembly formation
The unique feature of this proposal is its integrative vision of synthetic & systems biology, structural biology, cell biology, genetics, experiments and computation to establish a discovery platform to study IDRs in a cellular context. Since IdrSeq is modular and scalable, it can be readily extended to investigate a broad range of IDR functions, and adapted to other organisms. Elucidating the principles of sequence-function-gene relationship of IDRs holds enormous potential for synthetic biology. The discovery of genes that regulate IDR function has direct implications for human health by revealing novel therapeutic targets.
Summary
A large fraction of any eukaryotic genome (>40%) encodes protein segments that do not adopt a defined tertiary structure. These proteins or regions are called intrinsically disordered proteins/regions (IDPs/IDRs). IDRs are enriched in critical functions such as transcription and signaling, and have been linked with numerous diseases including neurodegeneration and cancer. In contrast to structured regions, the molecular principles behind the sequence-function relationship of IDRs remain poorly understood.
We propose to identify functional IDRs and discover genes that regulate their function using yeast as a cellular model. We will develop and apply a targeted, high-throughput approach called IdrSeq. This technology exploits next generation sequencing to simultaneously assay vast libraries of sequences (~millions) that code for IDRs by coupling IDR sequence (genotype) to a selectable function (phenotype) and identifying functional variants through a selection experiment.
Specifically, using IdrSeq, we aim to identify and characterize IDRs in a cellular context that can
(Aim 1) activate transcription, and discover genes that regulate IDR mediated transcription
(Aim 2) influence protein stability, and discover genes that regulate IDR mediated half-life
(Aim 3) form higher-order assemblies and discover genes that regulate assembly formation
The unique feature of this proposal is its integrative vision of synthetic & systems biology, structural biology, cell biology, genetics, experiments and computation to establish a discovery platform to study IDRs in a cellular context. Since IdrSeq is modular and scalable, it can be readily extended to investigate a broad range of IDR functions, and adapted to other organisms. Elucidating the principles of sequence-function-gene relationship of IDRs holds enormous potential for synthetic biology. The discovery of genes that regulate IDR function has direct implications for human health by revealing novel therapeutic targets.
Max ERC Funding
1 998 126 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
