Project acronym AAMDDR
Project DNA damage response and genome stability: The role of ATM, ATR and the Mre11 complex
Researcher (PI) Vincenzo Costanzo
Host Institution (HI) CANCER RESEARCH UK LBG
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Summary
Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Max ERC Funding
1 000 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym ACTINONSRF
Project MAL: an actin-regulated SRF transcriptional coactivator
Researcher (PI) Richard Treisman
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Advanced Grant (AdG), LS1, ERC-2010-AdG_20100317
Summary MAL: an actin-regulated SRF transcriptional coactivator
Recent years have seen a revitalised interest in the role of actin in nuclear processes, but the molecular mechanisms involved remain largely unexplored. We will elucidate the molecular basis for the actin-based control of the SRF transcriptional coactivator, MAL. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MAL, Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). MAL subcellular localisation and transcriptional activity responds to signal-induced changes in G-actin concentration, which are sensed by its actin-binding N-terminal RPEL domain. Members of a second family of RPEL proteins, the Phactrs, also exhibit actin-regulated nucleocytoplasmic shuttling. The proposal addresses the following novel features of actin biology:
¿ Actin as a transcriptional regulator
¿ Actin as a signalling molecule
¿ Actin-binding proteins as targets for regulation by actin, rather than regulators of actin function
We will analyse the sequences and proteins involved in actin-regulated nucleocytoplasmic shuttling, using structural biology and biochemistry to analyse its control by changes in actin-RPEL domain interactions. We will characterise the dynamics of shuttling, and develop reporters for changes in actin-MAL interaction for analysis of pathway activation in vivo. We will identify genes controlling MAL itself, and the balance between the nuclear and cytoplasmic actin pools. The mechanism by which actin represses transcriptional activation by MAL in the nucleus, and its relation to MAL phosphorylation, will be elucidated. Finally, we will map MRTF and TCF cofactor recruitment to SRF targets on a genome-wide scale, and identify the steps in transcription controlled by actin-MAL interaction.
Summary
MAL: an actin-regulated SRF transcriptional coactivator
Recent years have seen a revitalised interest in the role of actin in nuclear processes, but the molecular mechanisms involved remain largely unexplored. We will elucidate the molecular basis for the actin-based control of the SRF transcriptional coactivator, MAL. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MAL, Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). MAL subcellular localisation and transcriptional activity responds to signal-induced changes in G-actin concentration, which are sensed by its actin-binding N-terminal RPEL domain. Members of a second family of RPEL proteins, the Phactrs, also exhibit actin-regulated nucleocytoplasmic shuttling. The proposal addresses the following novel features of actin biology:
¿ Actin as a transcriptional regulator
¿ Actin as a signalling molecule
¿ Actin-binding proteins as targets for regulation by actin, rather than regulators of actin function
We will analyse the sequences and proteins involved in actin-regulated nucleocytoplasmic shuttling, using structural biology and biochemistry to analyse its control by changes in actin-RPEL domain interactions. We will characterise the dynamics of shuttling, and develop reporters for changes in actin-MAL interaction for analysis of pathway activation in vivo. We will identify genes controlling MAL itself, and the balance between the nuclear and cytoplasmic actin pools. The mechanism by which actin represses transcriptional activation by MAL in the nucleus, and its relation to MAL phosphorylation, will be elucidated. Finally, we will map MRTF and TCF cofactor recruitment to SRF targets on a genome-wide scale, and identify the steps in transcription controlled by actin-MAL interaction.
Max ERC Funding
1 889 995 €
Duration
Start date: 2011-10-01, End date: 2017-09-30
Project acronym AMYTOX
Project Amyloid fibril cytotoxicity: new insights from novel approaches
Researcher (PI) Sheena Radford
Host Institution (HI) UNIVERSITY OF LEEDS
Call Details Advanced Grant (AdG), LS1, ERC-2012-ADG_20120314
Summary Despite the discovery of amyloidosis more than a century ago, the molecular and cellular mechanisms of these devastating human disorders remain obscure. In addition to their involvement in disease, amyloid fibrils perform physiological functions, whilst others have potentials as biomaterials. To realise their use in nanotechnology and to enable the development of amyloid therapies, there is an urgent need to understand the molecular pathways of amyloid assembly and to determine how amyloid fibrils interact with cells and cellular components. The challenges lie in the transient nature and low population of aggregating species and the panoply of amyloid fibril structures. This molecular complexity renders identification of the culprits of amyloid disease impossible to achieve using traditional methods.
Here I propose a series of exciting experiments that aim to cast new light on the molecular and cellular mechanisms of amyloidosis by exploiting approaches capable of imaging individual protein molecules or single protein fibrils in vitro and in living cells. The proposal builds on new data from our laboratory that have shown that amyloid fibrils (disease-associated, functional and created from de novo designed sequences) kill cells by a mechanism that depends on fibril length and on cellular uptake. Specifically, I will (i) use single molecule fluorescence and non-covalent mass spectrometry and to determine why short fibril samples disrupt biological membranes more than their longer counterparts and electron tomography to determine, for the first time, the structural properties of cytotoxic fibril ends; (ii) develop single molecule force spectroscopy to probe the interactions between amyloid precursors, fibrils and cellular membranes; and (iii) develop cell biological assays to discover the biological mechanism(s) of amyloid-induced cell death and high resolution imaging and electron tomography to visualise amyloid fibrils in the act of killing living cells.
Summary
Despite the discovery of amyloidosis more than a century ago, the molecular and cellular mechanisms of these devastating human disorders remain obscure. In addition to their involvement in disease, amyloid fibrils perform physiological functions, whilst others have potentials as biomaterials. To realise their use in nanotechnology and to enable the development of amyloid therapies, there is an urgent need to understand the molecular pathways of amyloid assembly and to determine how amyloid fibrils interact with cells and cellular components. The challenges lie in the transient nature and low population of aggregating species and the panoply of amyloid fibril structures. This molecular complexity renders identification of the culprits of amyloid disease impossible to achieve using traditional methods.
Here I propose a series of exciting experiments that aim to cast new light on the molecular and cellular mechanisms of amyloidosis by exploiting approaches capable of imaging individual protein molecules or single protein fibrils in vitro and in living cells. The proposal builds on new data from our laboratory that have shown that amyloid fibrils (disease-associated, functional and created from de novo designed sequences) kill cells by a mechanism that depends on fibril length and on cellular uptake. Specifically, I will (i) use single molecule fluorescence and non-covalent mass spectrometry and to determine why short fibril samples disrupt biological membranes more than their longer counterparts and electron tomography to determine, for the first time, the structural properties of cytotoxic fibril ends; (ii) develop single molecule force spectroscopy to probe the interactions between amyloid precursors, fibrils and cellular membranes; and (iii) develop cell biological assays to discover the biological mechanism(s) of amyloid-induced cell death and high resolution imaging and electron tomography to visualise amyloid fibrils in the act of killing living cells.
Max ERC Funding
2 498 465 €
Duration
Start date: 2013-05-01, End date: 2019-04-30
Project acronym AORVM
Project The Effects of Aging on Object Representation in Visual Working Memory
Researcher (PI) James Robert Brockmole
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Call Details Starting Grant (StG), SH3, ERC-2007-StG
Summary One’s ability to remember visual material such as objects, faces, and spatial locations over a short period of time declines with age. The proposed research will examine whether these deficits are explained by a reduction in visual working memory (VWM) capacity, or an impairment in one’s ability to maintain, or ‘bind’ appropriate associations among pieces of related information. In this project successful binding is operationally defined as the proper recall or recognition of objects that are defined by the conjunction of multiple visual features. While tests of long-term memory have demonstrated that, despite preserved memory for isolated features, older adults have more difficulty remembering conjunctions of features, no research has yet investigated analogous age related binding deficits in VWM. This is a critical oversight because, given the current state of the science, it is unknown whether these deficits are specific to the long-term memory system, or if they originate in VWM. The project interweaves three strands of research that each investigate whether older adults have more difficulty creating, maintaining, and updating bound multi-feature object representations than younger adults. This theoretical program of enquiry will provide insight into the cognitive architecture of VWM and how this system changes with age, and its outcomes will have wide ranging multi-disciplinary applications in applied theory and intervention techniques that may reduce the adverse consequences of aging on memory.
Summary
One’s ability to remember visual material such as objects, faces, and spatial locations over a short period of time declines with age. The proposed research will examine whether these deficits are explained by a reduction in visual working memory (VWM) capacity, or an impairment in one’s ability to maintain, or ‘bind’ appropriate associations among pieces of related information. In this project successful binding is operationally defined as the proper recall or recognition of objects that are defined by the conjunction of multiple visual features. While tests of long-term memory have demonstrated that, despite preserved memory for isolated features, older adults have more difficulty remembering conjunctions of features, no research has yet investigated analogous age related binding deficits in VWM. This is a critical oversight because, given the current state of the science, it is unknown whether these deficits are specific to the long-term memory system, or if they originate in VWM. The project interweaves three strands of research that each investigate whether older adults have more difficulty creating, maintaining, and updating bound multi-feature object representations than younger adults. This theoretical program of enquiry will provide insight into the cognitive architecture of VWM and how this system changes with age, and its outcomes will have wide ranging multi-disciplinary applications in applied theory and intervention techniques that may reduce the adverse consequences of aging on memory.
Max ERC Funding
500 000 €
Duration
Start date: 2008-09-01, End date: 2011-08-31
Project acronym ARITHMUS
Project Peopling Europe: How data make a people
Researcher (PI) Evelyn Sharon Ruppert
Host Institution (HI) GOLDSMITHS' COLLEGE
Call Details Consolidator Grant (CoG), SH3, ERC-2013-CoG
Summary Who are the people of Europe? This question is facing statisticians as they grapple with standardising national census methods so that their numbers can be assembled into a European population. Yet, by so doing—intentionally or otherwise—they also contribute to the making of a European people. This, at least, is the central thesis of ARITHMUS. While typically framed as a methodological or statistical problem, the project approaches this as a practical and political problem of assembling multiple national populations into a European population and people.
Why is this both an urgent political and practical problem? Politically, Europe is said to be unable to address itself to a constituted polity and people, which is crucial to European integration. Practically, its efforts to constitute a European population are also being challenged by digital technologies, which are being used to diversify census methods and bringing into question the comparability of national population data. Consequently, over the next several years Eurostat and national statistical institutes are negotiating regulations for the 2020 census round towards ensuring 'Europe-wide comparability.'
ARITHMUS will follow this process and investigate the practices of statisticians as they juggle scientific independence, national autonomy and EU comparability to innovate census methods. It will then connect this practical work to political questions of the making and governing of a European people and polity. It will do so by going beyond state-of-the art scholarship on methods, politics and science and technology studies. Five case studies involving discourse analysis and ethnographic methods will investigate the situated practices of EU and national statisticians as they remake census methods, arguably the most fundamental changes since modern censuses were launched over two centuries ago. At the same time it will attend to how these practices affect the constitution of who are the people of Europe.
Summary
Who are the people of Europe? This question is facing statisticians as they grapple with standardising national census methods so that their numbers can be assembled into a European population. Yet, by so doing—intentionally or otherwise—they also contribute to the making of a European people. This, at least, is the central thesis of ARITHMUS. While typically framed as a methodological or statistical problem, the project approaches this as a practical and political problem of assembling multiple national populations into a European population and people.
Why is this both an urgent political and practical problem? Politically, Europe is said to be unable to address itself to a constituted polity and people, which is crucial to European integration. Practically, its efforts to constitute a European population are also being challenged by digital technologies, which are being used to diversify census methods and bringing into question the comparability of national population data. Consequently, over the next several years Eurostat and national statistical institutes are negotiating regulations for the 2020 census round towards ensuring 'Europe-wide comparability.'
ARITHMUS will follow this process and investigate the practices of statisticians as they juggle scientific independence, national autonomy and EU comparability to innovate census methods. It will then connect this practical work to political questions of the making and governing of a European people and polity. It will do so by going beyond state-of-the art scholarship on methods, politics and science and technology studies. Five case studies involving discourse analysis and ethnographic methods will investigate the situated practices of EU and national statisticians as they remake census methods, arguably the most fundamental changes since modern censuses were launched over two centuries ago. At the same time it will attend to how these practices affect the constitution of who are the people of Europe.
Max ERC Funding
1 833 649 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym ASSHURED
Project Analysing South-South Humanitarian Responses to Displacement from Syria: Views from Lebanon, Jordan and Turkey
Researcher (PI) Elena FIDDIAN-QASMIYEH
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), SH3, ERC-2016-STG
Summary Since 2012, over 4 million people have fled Syria in ‘the most dramatic humanitarian crisis that we have ever faced’ (UNHCR). By November 2015 there were 1,078,338 refugees from Syria in Lebanon, 630,776 in Jordan and 2,181,293 in Turkey. Humanitarian agencies and donor states from both the global North and the global South have funded and implemented aid programmes, and yet commentators have argued that civil society groups from the global South are the most significant actors supporting refugees in Lebanon, Jordan and Turkey. Whilst they are highly significant responses, however, major gaps in knowledge remain regarding the motivations, nature and implications of Southern-led responses to conflict-induced displacement. This project draws on multi-sited ethnographic and participatory research with refugees from Syria and their aid providers in Lebanon, Jordan and Turkey to critically examine why, how and with what effect actors from the South have responded to the displacement of refugees from Syria. The main research aims are:
1. identifying diverse models of Southern-led responses to conflict-induced displacement,
2. examining the (un)official motivations, nature and implications of Southern-led responses,
3. examining refugees’ experiences and perceptions of Southern-led responses,
4. exploring diverse Southern and Northern actors’ perceptions of Southern-led responses,
5. tracing the implications of Southern-led initiatives for humanitarian theory and practice.
Based on a critical theoretical framework inspired by post-colonial and feminist approaches, the project contributes to theories of humanitarianism and debates regarding donor-recipient relations and refugees’ agency in displacement situations. It will also inform the development of policies to most appropriately address refugees’ needs and rights. This highly topical and innovative project thus has far-reaching implications for refugees and local communities, academics, policy-makers and practitioners.
Summary
Since 2012, over 4 million people have fled Syria in ‘the most dramatic humanitarian crisis that we have ever faced’ (UNHCR). By November 2015 there were 1,078,338 refugees from Syria in Lebanon, 630,776 in Jordan and 2,181,293 in Turkey. Humanitarian agencies and donor states from both the global North and the global South have funded and implemented aid programmes, and yet commentators have argued that civil society groups from the global South are the most significant actors supporting refugees in Lebanon, Jordan and Turkey. Whilst they are highly significant responses, however, major gaps in knowledge remain regarding the motivations, nature and implications of Southern-led responses to conflict-induced displacement. This project draws on multi-sited ethnographic and participatory research with refugees from Syria and their aid providers in Lebanon, Jordan and Turkey to critically examine why, how and with what effect actors from the South have responded to the displacement of refugees from Syria. The main research aims are:
1. identifying diverse models of Southern-led responses to conflict-induced displacement,
2. examining the (un)official motivations, nature and implications of Southern-led responses,
3. examining refugees’ experiences and perceptions of Southern-led responses,
4. exploring diverse Southern and Northern actors’ perceptions of Southern-led responses,
5. tracing the implications of Southern-led initiatives for humanitarian theory and practice.
Based on a critical theoretical framework inspired by post-colonial and feminist approaches, the project contributes to theories of humanitarianism and debates regarding donor-recipient relations and refugees’ agency in displacement situations. It will also inform the development of policies to most appropriately address refugees’ needs and rights. This highly topical and innovative project thus has far-reaching implications for refugees and local communities, academics, policy-makers and practitioners.
Max ERC Funding
1 498 069 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
Project acronym ASYFAIR
Project Fair and Consistent Border Controls? A Critical, Multi-methodological and Interdisciplinary Study of Asylum Adjudication in Europe
Researcher (PI) Nicholas Mark Gill
Host Institution (HI) THE UNIVERSITY OF EXETER
Call Details Starting Grant (StG), SH3, ERC-2015-STG
Summary ‘Consistency’ is regularly cited as a desirable attribute of border control, but it has received little critical social scientific attention. This inter-disciplinary project, at the inter-face between critical human geography, border studies and law, will scrutinise the consistency of European asylum adjudication in order to develop richer theoretical understanding of this lynchpin concept. It will move beyond the administrative legal concepts of substantive and procedural consistency by advancing a three-fold conceptualisation of consistency – as everyday practice, discursive deployment of facts and disciplinary technique. In order to generate productive intellectual tension it will also employ an explicitly antagonistic conceptualisation of the relationship between geography and law that views law as seeking to constrain and systematise lived space. The project will employ an innovative combination of methodologies that will produce unique and rich data sets including quantitative analysis, multi-sited legal ethnography, discourse analysis and interviews, and the findings are likely to be of interest both to academic communities like geographers, legal and border scholars and to policy makers and activists working in border control settings. In 2013 the Common European Asylum System (CEAS) was launched to standardise the procedures of asylum determination. But as yet no sustained multi-methodological assessment of the claims of consistency inherent to the CEAS has been carried out. This project offers not only the opportunity to assess progress towards harmonisation of asylum determination processes in Europe, but will also provide a new conceptual framework with which to approach the dilemmas and risks of inconsistency in an area of law fraught with political controversy and uncertainty around the world. Most fundamentally, the project promises to debunk the myths surrounding the possibility of fair and consistent border controls in Europe and elsewhere.
Summary
‘Consistency’ is regularly cited as a desirable attribute of border control, but it has received little critical social scientific attention. This inter-disciplinary project, at the inter-face between critical human geography, border studies and law, will scrutinise the consistency of European asylum adjudication in order to develop richer theoretical understanding of this lynchpin concept. It will move beyond the administrative legal concepts of substantive and procedural consistency by advancing a three-fold conceptualisation of consistency – as everyday practice, discursive deployment of facts and disciplinary technique. In order to generate productive intellectual tension it will also employ an explicitly antagonistic conceptualisation of the relationship between geography and law that views law as seeking to constrain and systematise lived space. The project will employ an innovative combination of methodologies that will produce unique and rich data sets including quantitative analysis, multi-sited legal ethnography, discourse analysis and interviews, and the findings are likely to be of interest both to academic communities like geographers, legal and border scholars and to policy makers and activists working in border control settings. In 2013 the Common European Asylum System (CEAS) was launched to standardise the procedures of asylum determination. But as yet no sustained multi-methodological assessment of the claims of consistency inherent to the CEAS has been carried out. This project offers not only the opportunity to assess progress towards harmonisation of asylum determination processes in Europe, but will also provide a new conceptual framework with which to approach the dilemmas and risks of inconsistency in an area of law fraught with political controversy and uncertainty around the world. Most fundamentally, the project promises to debunk the myths surrounding the possibility of fair and consistent border controls in Europe and elsewhere.
Max ERC Funding
1 252 067 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym ATG9_SOLVES_IT
Project In vitro high resolution reconstitution of autophagosome nucleation and expansion catalyzed byATG9
Researcher (PI) Sharon TOOZE
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Advanced Grant (AdG), LS1, ERC-2017-ADG
Summary Autophagy is a conserved, lysosomal-mediated pathway required for cell homeostasis and survival. It is controlled by the master regulators of energy (AMPK) and growth (TORC1) and mediated by the ATG (autophagy) proteins. Deregulation of autophagy is implicated in cancer, immunity, infection, aging and neurodegeneration. Autophagosomes form and expand using membranes from the secretory and endocytic pathways but how this occurs is not understood. ATG9, the only transmembrane ATG protein traffics through the cell in vesicles, and is essential for rapid initiation and expansion of the membranes which form the autophagosome. Crucially, how ATG9 functions is unknown. I will determine how ATG9 initiates the formation and expansion of the autophagosome by amino acid starvation through a molecular dissection of proteins resident in ATG9 vesicles which modulate the composition and property of the initiating membrane. I will employ high resolution light and electron microscopy to characterize the nucleation of the autophagosome, proximity-specific biotinylation and quantitative Mass Spectrometry to uncover the proteome required for the function of the ATG9, and optogenetic tools to acutely regulate signaling lipids. Lastly, with our tools and knowledge I will develop an in vitro reconstitution system to define at a molecular level how ATG9 vesicle proteins, membranes that interact with ATG9 vesicles, and other accessory ATG components nucleate and form an autophagosome. In vitro reconstitution of autophagosomes will be assayed biochemically, and by correlative light and cryo-EM and cryo-EM tomography, while functional reconstitution of autophagy will be tested by selective cargo recruitment. The development of a reconstituted system and identification proteins and lipids which are key components for autophagosome formation will provide a means to identify a new generation of targets for translational work leading to manipulation of autophagy for disease related therapies.
Summary
Autophagy is a conserved, lysosomal-mediated pathway required for cell homeostasis and survival. It is controlled by the master regulators of energy (AMPK) and growth (TORC1) and mediated by the ATG (autophagy) proteins. Deregulation of autophagy is implicated in cancer, immunity, infection, aging and neurodegeneration. Autophagosomes form and expand using membranes from the secretory and endocytic pathways but how this occurs is not understood. ATG9, the only transmembrane ATG protein traffics through the cell in vesicles, and is essential for rapid initiation and expansion of the membranes which form the autophagosome. Crucially, how ATG9 functions is unknown. I will determine how ATG9 initiates the formation and expansion of the autophagosome by amino acid starvation through a molecular dissection of proteins resident in ATG9 vesicles which modulate the composition and property of the initiating membrane. I will employ high resolution light and electron microscopy to characterize the nucleation of the autophagosome, proximity-specific biotinylation and quantitative Mass Spectrometry to uncover the proteome required for the function of the ATG9, and optogenetic tools to acutely regulate signaling lipids. Lastly, with our tools and knowledge I will develop an in vitro reconstitution system to define at a molecular level how ATG9 vesicle proteins, membranes that interact with ATG9 vesicles, and other accessory ATG components nucleate and form an autophagosome. In vitro reconstitution of autophagosomes will be assayed biochemically, and by correlative light and cryo-EM and cryo-EM tomography, while functional reconstitution of autophagy will be tested by selective cargo recruitment. The development of a reconstituted system and identification proteins and lipids which are key components for autophagosome formation will provide a means to identify a new generation of targets for translational work leading to manipulation of autophagy for disease related therapies.
Max ERC Funding
2 121 055 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym ATMINDDR
Project ATMINistrating ATM signalling: exploring the significance of ATM regulation by ATMIN
Researcher (PI) Axel Behrens
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary ATM is the protein kinase that is mutated in the hereditary autosomal recessive disease ataxia telangiectasia (A-T). A-T patients display immune deficiencies, cancer predisposition and radiosensitivity. The molecular role of ATM is to respond to DNA damage by phosphorylating its substrates, thereby promoting repair of damage or arresting the cell cycle. Following the induction of double-strand breaks (DSBs), the NBS1 protein is required for activation of ATM. But ATM can also be activated in the absence of DNA damage. Treatment of cultured cells with hypotonic stress leads to the activation of ATM, presumably due to changes in chromatin structure. We have recently described a second ATM cofactor, ATMIN (ATM INteractor). ATMIN is dispensable for DSBs-induced ATM signalling, but ATM activation following hypotonic stress is mediated by ATMIN. While the biological role of ATM activation by DSBs and NBS1 is well established, the significance, if any, of ATM activation by ATMIN and changes in chromatin was up to now completely enigmatic.
ATM is required for class switch recombination (CSR) and the suppression of translocations in B cells. In order to determine whether ATMIN is required for any of the physiological functions of ATM, we generated a conditional knock-out mouse model for ATMIN. ATM signaling was dramatically reduced following osmotic stress in ATMIN-mutant B cells. ATMIN deficiency led to impaired CSR, and consequently ATMIN-mutant mice developed B cell lymphomas. Thus ablation of ATMIN resulted in a severe defect in ATM function. Our data strongly argue for the existence of a second NBS1-independent mode of ATM activation that is physiologically relevant. While a large amount of scientific effort has gone into characterising ATM signaling triggered by DSBs, essentially nothing is known about NBS1-independent ATM signaling. The experiments outlined in this proposal have the aim to identify and understand the molecular pathway of ATMIN-dependent ATM signaling.
Summary
ATM is the protein kinase that is mutated in the hereditary autosomal recessive disease ataxia telangiectasia (A-T). A-T patients display immune deficiencies, cancer predisposition and radiosensitivity. The molecular role of ATM is to respond to DNA damage by phosphorylating its substrates, thereby promoting repair of damage or arresting the cell cycle. Following the induction of double-strand breaks (DSBs), the NBS1 protein is required for activation of ATM. But ATM can also be activated in the absence of DNA damage. Treatment of cultured cells with hypotonic stress leads to the activation of ATM, presumably due to changes in chromatin structure. We have recently described a second ATM cofactor, ATMIN (ATM INteractor). ATMIN is dispensable for DSBs-induced ATM signalling, but ATM activation following hypotonic stress is mediated by ATMIN. While the biological role of ATM activation by DSBs and NBS1 is well established, the significance, if any, of ATM activation by ATMIN and changes in chromatin was up to now completely enigmatic.
ATM is required for class switch recombination (CSR) and the suppression of translocations in B cells. In order to determine whether ATMIN is required for any of the physiological functions of ATM, we generated a conditional knock-out mouse model for ATMIN. ATM signaling was dramatically reduced following osmotic stress in ATMIN-mutant B cells. ATMIN deficiency led to impaired CSR, and consequently ATMIN-mutant mice developed B cell lymphomas. Thus ablation of ATMIN resulted in a severe defect in ATM function. Our data strongly argue for the existence of a second NBS1-independent mode of ATM activation that is physiologically relevant. While a large amount of scientific effort has gone into characterising ATM signaling triggered by DSBs, essentially nothing is known about NBS1-independent ATM signaling. The experiments outlined in this proposal have the aim to identify and understand the molecular pathway of ATMIN-dependent ATM signaling.
Max ERC Funding
1 499 881 €
Duration
Start date: 2012-02-01, End date: 2018-01-31
Project acronym BAPS
Project Bayesian Agent-based Population Studies: Transforming Simulation Models of Human Migration
Researcher (PI) Jakub KAZIMIERZ BIJAK
Host Institution (HI) UNIVERSITY OF SOUTHAMPTON
Call Details Consolidator Grant (CoG), SH3, ERC-2016-COG
Summary The aim of BAPS is to develop a ground-breaking simulation model of international migration, based on a population of intelligent, cognitive agents, their social networks and institutions, all interacting with one another. The project will transform the study of migration – one of the most uncertain population processes and a top-priority EU policy area – by offering a step change in the way it can be understood, predicted and managed. In this way, BAPS will effectively integrate behavioural and social theory with modelling.
To develop micro-foundations for migration studies, model design will follow cutting-edge developments in demography, statistics, cognitive psychology and computer science. BAPS will also offer a pioneering environment for applying the findings in practice through a bespoke modelling language. Bayesian statistical principles will be used to design innovative computer experiments, and learn about modelling the simulated individuals and the way they make decisions.
In BAPS, we will collate available information for migration models; build and test the simulations by applying experimental design principles to enhance our knowledge of migration processes; collect information on the underpinning decision-making mechanisms through psychological experiments; and design software for implementing Bayesian agent-based models in practice. The project will use various information sources to build models bottom-up, filling an important epistemological gap in demography.
BAPS will be carried out by the Allianz European Demographer 2015, recognised as a leader in the field for methodological innovation, directing an interdisciplinary team with expertise in demography, agent-based models, statistical analysis of uncertainty, meta-cognition, and computer simulations. The project will open up exciting research possibilities beyond demography, and will generate both academic and practical impact, offering methodological advice for policy-relevant simulations.
Summary
The aim of BAPS is to develop a ground-breaking simulation model of international migration, based on a population of intelligent, cognitive agents, their social networks and institutions, all interacting with one another. The project will transform the study of migration – one of the most uncertain population processes and a top-priority EU policy area – by offering a step change in the way it can be understood, predicted and managed. In this way, BAPS will effectively integrate behavioural and social theory with modelling.
To develop micro-foundations for migration studies, model design will follow cutting-edge developments in demography, statistics, cognitive psychology and computer science. BAPS will also offer a pioneering environment for applying the findings in practice through a bespoke modelling language. Bayesian statistical principles will be used to design innovative computer experiments, and learn about modelling the simulated individuals and the way they make decisions.
In BAPS, we will collate available information for migration models; build and test the simulations by applying experimental design principles to enhance our knowledge of migration processes; collect information on the underpinning decision-making mechanisms through psychological experiments; and design software for implementing Bayesian agent-based models in practice. The project will use various information sources to build models bottom-up, filling an important epistemological gap in demography.
BAPS will be carried out by the Allianz European Demographer 2015, recognised as a leader in the field for methodological innovation, directing an interdisciplinary team with expertise in demography, agent-based models, statistical analysis of uncertainty, meta-cognition, and computer simulations. The project will open up exciting research possibilities beyond demography, and will generate both academic and practical impact, offering methodological advice for policy-relevant simulations.
Max ERC Funding
1 455 590 €
Duration
Start date: 2017-06-01, End date: 2021-05-31
