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 ALZSYN
Project Imaging synaptic contributors to dementia
Researcher (PI) Tara Spires-Jones
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Country United Kingdom
Call Details Consolidator Grant (CoG), LS5, ERC-2015-CoG
Summary Alzheimer's disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimer’s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimer’s disease by integrating human and model studies of synapses. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However the cascade leading from changes in amyloid to widespread tau pathology and neurodegeneration remain unclear. Synapse loss is the strongest pathological correlate of dementia in Alzheimer’s, and mounting evidence suggests that synapse degeneration plays a key role in causing cognitive decline. Here I propose to test the hypothesis that the amyloid cascade begins at the synapse leading to tau pathology, synapse dysfunction and loss, and ultimately neural circuit collapse causing cognitive impairment. The team will use cutting-edge multiphoton and array tomography imaging techniques to test mechanisms downstream of amyloid beta at synapses, and determine whether intervening in the cascade allows recovery of synapse structure and function. Importantly, I will combine studies in robust models of familial Alzheimer’s disease with studies in postmortem human brain to confirm relevance of our mechanistic studies to human disease. Finally, human stem cell derived neurons will be used to test mechanisms and potential therapeutics in neurons expressing the human proteome. Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimer’s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in today’s health care system.
Summary
Alzheimer's disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimer’s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimer’s disease by integrating human and model studies of synapses. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However the cascade leading from changes in amyloid to widespread tau pathology and neurodegeneration remain unclear. Synapse loss is the strongest pathological correlate of dementia in Alzheimer’s, and mounting evidence suggests that synapse degeneration plays a key role in causing cognitive decline. Here I propose to test the hypothesis that the amyloid cascade begins at the synapse leading to tau pathology, synapse dysfunction and loss, and ultimately neural circuit collapse causing cognitive impairment. The team will use cutting-edge multiphoton and array tomography imaging techniques to test mechanisms downstream of amyloid beta at synapses, and determine whether intervening in the cascade allows recovery of synapse structure and function. Importantly, I will combine studies in robust models of familial Alzheimer’s disease with studies in postmortem human brain to confirm relevance of our mechanistic studies to human disease. Finally, human stem cell derived neurons will be used to test mechanisms and potential therapeutics in neurons expressing the human proteome. Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimer’s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in today’s health care system.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
Project acronym ARIADNE
Project ARgon ImAging DetectioN chambEr
Researcher (PI) Konstantinos Mavrokoridis
Host Institution (HI) THE UNIVERSITY OF LIVERPOOL
Country United Kingdom
Call Details Starting Grant (StG), PE2, ERC-2015-STG
Summary This proposal outlines a plan to combine Charge Couple Device (CCD) camera technologies with two-phase Liquid Argon Time Projection Chambers (LAr TPCs) utilising THick Gas Electron Multipliers (THGEMs) to evolve a next generation neutrino detector. This will be an entirely new readout option, and will open the prospect of revolutionary discoveries in fundamental particle physics. Furthermore, the Compton imaging power of this technology will be developed, which will have diverse applications in novel medical imaging techniques and detection of concealed nuclear materials.
Colossal LAr TPCs are the future for long-baseline-neutrino-oscillation physics around which the international neutrino community is rallying, with the common goal of discovering new physics beyond the Standard Model, which holds the key to our understanding of phenomena such as dark matter and the matter-antimatter asymmetry.
I have successfully provided a first demonstration of photographic capturing of muon tracks and single gammas interacting in the Liverpool 40 l LAr TPC using a CCD camera and THGEM. I propose an ambitious project of extensive research to mature this innovative LAr optical readout technology. I will construct a 650 l LAr TPC with integrated CCD/THGEM readout, capable of containing sufficient tracking information for full development and characterisation of this novel detector, with the goal of realising this game-changing technology in the planned future giant LAr TPCs. Camera readout can replace the current charge readout technology and associated scalability complications, and the excellent energy thresholds will enhance detector performance as well as extend research avenues to lower energy fundamental physics.
Also, I will explore the Compton imaging capability of LAr CCD/THGEM technology; the superiority of the energy threshold and spatial resolution of this system can offer significant advancement to medical imaging and the detection of concealed nuclear materials.
Summary
This proposal outlines a plan to combine Charge Couple Device (CCD) camera technologies with two-phase Liquid Argon Time Projection Chambers (LAr TPCs) utilising THick Gas Electron Multipliers (THGEMs) to evolve a next generation neutrino detector. This will be an entirely new readout option, and will open the prospect of revolutionary discoveries in fundamental particle physics. Furthermore, the Compton imaging power of this technology will be developed, which will have diverse applications in novel medical imaging techniques and detection of concealed nuclear materials.
Colossal LAr TPCs are the future for long-baseline-neutrino-oscillation physics around which the international neutrino community is rallying, with the common goal of discovering new physics beyond the Standard Model, which holds the key to our understanding of phenomena such as dark matter and the matter-antimatter asymmetry.
I have successfully provided a first demonstration of photographic capturing of muon tracks and single gammas interacting in the Liverpool 40 l LAr TPC using a CCD camera and THGEM. I propose an ambitious project of extensive research to mature this innovative LAr optical readout technology. I will construct a 650 l LAr TPC with integrated CCD/THGEM readout, capable of containing sufficient tracking information for full development and characterisation of this novel detector, with the goal of realising this game-changing technology in the planned future giant LAr TPCs. Camera readout can replace the current charge readout technology and associated scalability complications, and the excellent energy thresholds will enhance detector performance as well as extend research avenues to lower energy fundamental physics.
Also, I will explore the Compton imaging capability of LAr CCD/THGEM technology; the superiority of the energy threshold and spatial resolution of this system can offer significant advancement to medical imaging and the detection of concealed nuclear materials.
Max ERC Funding
1 837 911 €
Duration
Start date: 2016-03-01, End date: 2021-08-31
Project acronym BAYNET
Project Bayesian Networks and Non-Rational Expectations
Researcher (PI) Ran SPIEGLER
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Country United Kingdom
Call Details Advanced Grant (AdG), SH1, ERC-2015-AdG
Summary "This project will develop a new framework for modeling economic agents having ""boundedly rational expectations"" (BRE). It is based on the concept of Bayesian networks (more generally, graphical models), borrowed from statistics and AI. In the framework's basic version, an agent is characterized by a directed acyclic graph (DAG) over the set of all relevant random variables. The DAG is the agent's ""type"" – it represents how he systematically distorts any objective probability distribution into a subjective belief. Technically, the distortion takes the form of the standard Bayesian-network factorization formula given by the agent's DAG. The agent's choice is modeled as a ""personal equilibrium"", because his subjective belief regarding the implications of his actions can vary with his own long-run behavior. The DAG representation unifies and simplifies existing models of BRE, subsuming them as special cases corresponding to distinct graphical representations. It captures hitherto-unmodeled fallacies such as reverse causation. The framework facilitates behavioral characterizations of general classes of models of BRE and expands their applicability. I will demonstrate this with applications to monetary policy, behavioral I.O., asset pricing, etc. I will extend the basic formalism to multi-agent environments, addressing issues beyond the reach of current models of BRE (e.g., formalizing the notion of ""high-order"" limited understanding of statistical regularities). Finally, I will seek a learning foundation for the graphical representation of BRE, in the sense that it will capture how the agent extrapolates his belief from a dataset (drawn from the objective distribution) containing ""missing values"", via some intuitive ""imputation method"". This part, too, borrows ideas from statistics and AI, further demonstrating the project's interdisciplinary nature."
Summary
"This project will develop a new framework for modeling economic agents having ""boundedly rational expectations"" (BRE). It is based on the concept of Bayesian networks (more generally, graphical models), borrowed from statistics and AI. In the framework's basic version, an agent is characterized by a directed acyclic graph (DAG) over the set of all relevant random variables. The DAG is the agent's ""type"" – it represents how he systematically distorts any objective probability distribution into a subjective belief. Technically, the distortion takes the form of the standard Bayesian-network factorization formula given by the agent's DAG. The agent's choice is modeled as a ""personal equilibrium"", because his subjective belief regarding the implications of his actions can vary with his own long-run behavior. The DAG representation unifies and simplifies existing models of BRE, subsuming them as special cases corresponding to distinct graphical representations. It captures hitherto-unmodeled fallacies such as reverse causation. The framework facilitates behavioral characterizations of general classes of models of BRE and expands their applicability. I will demonstrate this with applications to monetary policy, behavioral I.O., asset pricing, etc. I will extend the basic formalism to multi-agent environments, addressing issues beyond the reach of current models of BRE (e.g., formalizing the notion of ""high-order"" limited understanding of statistical regularities). Finally, I will seek a learning foundation for the graphical representation of BRE, in the sense that it will capture how the agent extrapolates his belief from a dataset (drawn from the objective distribution) containing ""missing values"", via some intuitive ""imputation method"". This part, too, borrows ideas from statistics and AI, further demonstrating the project's interdisciplinary nature."
Max ERC Funding
1 379 288 €
Duration
Start date: 2016-07-01, End date: 2022-06-30
Project acronym BEEHIVE
Project Bridging the Evolution and Epidemiology of HIV in Europe
Researcher (PI) Christopher Fraser
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Advanced Grant (AdG), LS2, ERC-2013-ADG
Summary The aim of the BEEHIVE project is to generate novel insight into HIV biology, evolution and epidemiology, leveraging next-generation high-throughput sequencing and bioinformatics to produce and analyse whole-genomes of viruses from approximately 3,000 European HIV-1 infected patients. These patients have known dates of infection spread over the last 25 years, good clinical follow up, and a wide range of clinical prognostic indicators and outcomes. The primary objective is to discover the viral genetic determinants of severity of infection and set-point viral load. This primary objective is high-risk & blue-skies: there is ample indirect evidence of polymorphisms that alter virulence, but they have never been identified, and it is not known how easy they are to discover. However, the project is also high-reward: it could lead to a substantial shift in the understanding of HIV disease.
Technologically, the BEEHIVE project will deliver new approaches for undertaking whole genome association studies on RNA viruses, including delivering an innovative high-throughput bioinformatics pipeline for handling genetically diverse viral quasi-species data (with viral diversity both within and between infected patients).
The project also includes secondary and tertiary objectives that address critical open questions in HIV epidemiology and evolution. The secondary objective is to use viral genetic sequences allied to mathematical epidemic models to better understand the resurgent European epidemic amongst high-risk groups, especially men who have sex with men. The aim will not just be to establish who is at risk of infection, which is known from conventional epidemiological approaches, but also to characterise the risk factors for onwards transmission of the virus. Tertiary objectives involve understanding the relationship between the genetic diversity within viral samples, indicative of on-going evolution or dual infections, to clinical outcomes.
Summary
The aim of the BEEHIVE project is to generate novel insight into HIV biology, evolution and epidemiology, leveraging next-generation high-throughput sequencing and bioinformatics to produce and analyse whole-genomes of viruses from approximately 3,000 European HIV-1 infected patients. These patients have known dates of infection spread over the last 25 years, good clinical follow up, and a wide range of clinical prognostic indicators and outcomes. The primary objective is to discover the viral genetic determinants of severity of infection and set-point viral load. This primary objective is high-risk & blue-skies: there is ample indirect evidence of polymorphisms that alter virulence, but they have never been identified, and it is not known how easy they are to discover. However, the project is also high-reward: it could lead to a substantial shift in the understanding of HIV disease.
Technologically, the BEEHIVE project will deliver new approaches for undertaking whole genome association studies on RNA viruses, including delivering an innovative high-throughput bioinformatics pipeline for handling genetically diverse viral quasi-species data (with viral diversity both within and between infected patients).
The project also includes secondary and tertiary objectives that address critical open questions in HIV epidemiology and evolution. The secondary objective is to use viral genetic sequences allied to mathematical epidemic models to better understand the resurgent European epidemic amongst high-risk groups, especially men who have sex with men. The aim will not just be to establish who is at risk of infection, which is known from conventional epidemiological approaches, but also to characterise the risk factors for onwards transmission of the virus. Tertiary objectives involve understanding the relationship between the genetic diversity within viral samples, indicative of on-going evolution or dual infections, to clinical outcomes.
Max ERC Funding
2 499 739 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym BESTDECISION
Project "Behavioural Economics and Strategic Decision Making: Theory, Empirics, and Experiments"
Researcher (PI) Vincent Paul Crawford
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Advanced Grant (AdG), SH1, ERC-2013-ADG
Summary "I will study questions of central microeconomic importance via interwoven theoretical, empirical, and experimental analyses, from a behavioural perspective combining standard methods with assumptions that better reflect evidence on behaviour and psychological insights. The contributions of behavioural economics have been widely recognized, but the benefits of its insights are far from fully realized. I propose four lines of inquiry that focus on how institutions interact with cognition and behaviour, chosen for their potential to reshape our understanding of important questions and their synergies across lines.
The first line will study nonparametric identification and estimation of reference-dependent versions of the standard microeconomic model of consumer demand or labour supply, the subject of hundreds of empirical studies and perhaps the single most important model in microeconomics. It will allow such studies to consider relevant behavioural factors without imposing structural assumptions as in previous work.
The second line will analyze history-dependent learning in financial crises theoretically and experimentally, with the goal of quantifying how market structure influences the likelihood of a crisis.
The third line will study strategic thinking experimentally, using a powerful new design that links subjects’ searches for hidden payoff information (“eye-movements”) much more directly to thinking.
The fourth line will significantly advance Myerson and Satterthwaite’s analyses of optimal design of bargaining rules and auctions, which first went beyond the analysis of given institutions to study what is possible by designing new institutions, replacing their equilibrium assumption with a nonequilibrium model that is well supported by experiments.
The synergies among these four lines’ theoretical analyses, empirical methods, and data analyses will accelerate progress on each line well beyond what would be possible in a piecemeal approach."
Summary
"I will study questions of central microeconomic importance via interwoven theoretical, empirical, and experimental analyses, from a behavioural perspective combining standard methods with assumptions that better reflect evidence on behaviour and psychological insights. The contributions of behavioural economics have been widely recognized, but the benefits of its insights are far from fully realized. I propose four lines of inquiry that focus on how institutions interact with cognition and behaviour, chosen for their potential to reshape our understanding of important questions and their synergies across lines.
The first line will study nonparametric identification and estimation of reference-dependent versions of the standard microeconomic model of consumer demand or labour supply, the subject of hundreds of empirical studies and perhaps the single most important model in microeconomics. It will allow such studies to consider relevant behavioural factors without imposing structural assumptions as in previous work.
The second line will analyze history-dependent learning in financial crises theoretically and experimentally, with the goal of quantifying how market structure influences the likelihood of a crisis.
The third line will study strategic thinking experimentally, using a powerful new design that links subjects’ searches for hidden payoff information (“eye-movements”) much more directly to thinking.
The fourth line will significantly advance Myerson and Satterthwaite’s analyses of optimal design of bargaining rules and auctions, which first went beyond the analysis of given institutions to study what is possible by designing new institutions, replacing their equilibrium assumption with a nonequilibrium model that is well supported by experiments.
The synergies among these four lines’ theoretical analyses, empirical methods, and data analyses will accelerate progress on each line well beyond what would be possible in a piecemeal approach."
Max ERC Funding
1 985 373 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym BPI
Project Bayesian Peer Influence: Group Beliefs, Polarisation and Segregation
Researcher (PI) Gilat Levy
Host Institution (HI) LONDON SCHOOL OF ECONOMICS AND POLITICAL SCIENCE
Country United Kingdom
Call Details Consolidator Grant (CoG), SH1, ERC-2015-CoG
Summary "The objective of this research agenda is to provide a new framework to model and analyze dynamics of group beliefs, in order to study phenomena such as group polarization, segregation and inter-group discrimination. We introduce a simple new heuristic, the Bayesian Peer Influence heuristic (BPI), which is based on rational foundations and captures how individuals are influenced by others' beliefs. We will explore the theoretical properties of this heuristic, and apply the model to analyze the implications of belief dynamics on social interactions.
Understanding the formation and evolution of beliefs in groups is an important aspect of many economic applications, such as labour market discrimination. The beliefs that different groups of people have about members of other groups should be central to any theory or empirical investigation of this topic. At the same time, economic models of segregation and discrimination typically do not focus on the evolution and dynamics of group beliefs that allow for such phenomena. There is therefore a need for new tools of analysis for incorporating the dynamics of group beliefs; this is particularly important in order to understand the full implications of policy interventions which often intend to ""educate the public''. The BPI fills this gap in the literature by offering a tractable and natural heuristic for group communication.
Our aim is to study the theoretical properties of the BPI, as well as its applications to the dynamics of group behavior. Our plan is to: (i) Analyze rational learning from others’ beliefs and characterise the BPI. (ii) Use the BPI to account for cognitive biases in information processing. (iii) Use the BPI to analyze the diffusion of beliefs in social networks. (iv) Apply the BPI to understand the relation between belief polarization, segregation in education and labour market discrimination. (v) Apply the BPI to understand the relation between belief polarization and political outcomes."
Summary
"The objective of this research agenda is to provide a new framework to model and analyze dynamics of group beliefs, in order to study phenomena such as group polarization, segregation and inter-group discrimination. We introduce a simple new heuristic, the Bayesian Peer Influence heuristic (BPI), which is based on rational foundations and captures how individuals are influenced by others' beliefs. We will explore the theoretical properties of this heuristic, and apply the model to analyze the implications of belief dynamics on social interactions.
Understanding the formation and evolution of beliefs in groups is an important aspect of many economic applications, such as labour market discrimination. The beliefs that different groups of people have about members of other groups should be central to any theory or empirical investigation of this topic. At the same time, economic models of segregation and discrimination typically do not focus on the evolution and dynamics of group beliefs that allow for such phenomena. There is therefore a need for new tools of analysis for incorporating the dynamics of group beliefs; this is particularly important in order to understand the full implications of policy interventions which often intend to ""educate the public''. The BPI fills this gap in the literature by offering a tractable and natural heuristic for group communication.
Our aim is to study the theoretical properties of the BPI, as well as its applications to the dynamics of group behavior. Our plan is to: (i) Analyze rational learning from others’ beliefs and characterise the BPI. (ii) Use the BPI to account for cognitive biases in information processing. (iii) Use the BPI to analyze the diffusion of beliefs in social networks. (iv) Apply the BPI to understand the relation between belief polarization, segregation in education and labour market discrimination. (v) Apply the BPI to understand the relation between belief polarization and political outcomes."
Max ERC Funding
1 662 942 €
Duration
Start date: 2016-08-01, End date: 2022-01-31
Project acronym CARDIOREDOX
Project Redox sensing and signalling in cardiovascular health and disease
Researcher (PI) Philip Eaton
Host Institution (HI) KING'S COLLEGE LONDON
Country United Kingdom
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary "We want to determine how oxidants are sensed and transduced into a biological effect within the cardiovascular system. The proposed work will focus on thiol-based redox sensors, defining their role in heart and blood vessel function during health and disease. Although this laboratory has studied the molecular basis of redox signaling for more than a decade, the subject is still in its relative infancy with considerable scope for major advances. Oxidant signaling remains a ‘hot topic’ with high profile studies confirming a fundamental role for redox control of protein and cellular function continuing to emerge. The molecular basis of redox sensing is the reaction of an oxidant with target proteins. This gives rise to oxidative post-translational modifications, most commonly of cysteinyl thiols, potentially altering the activity of proteins to regulate cell or tissue function. One of the reasons there are so many unanswered questions about redox sensing and signaling is the diversity of oxidant molecules produced by cells that can interact with sensor proteins to alter their function. This application is aimed at extending our knowledge of redox sensing and signalling, allowing us to define its importance in cardiovascular health and disease."
Summary
"We want to determine how oxidants are sensed and transduced into a biological effect within the cardiovascular system. The proposed work will focus on thiol-based redox sensors, defining their role in heart and blood vessel function during health and disease. Although this laboratory has studied the molecular basis of redox signaling for more than a decade, the subject is still in its relative infancy with considerable scope for major advances. Oxidant signaling remains a ‘hot topic’ with high profile studies confirming a fundamental role for redox control of protein and cellular function continuing to emerge. The molecular basis of redox sensing is the reaction of an oxidant with target proteins. This gives rise to oxidative post-translational modifications, most commonly of cysteinyl thiols, potentially altering the activity of proteins to regulate cell or tissue function. One of the reasons there are so many unanswered questions about redox sensing and signaling is the diversity of oxidant molecules produced by cells that can interact with sensor proteins to alter their function. This application is aimed at extending our knowledge of redox sensing and signalling, allowing us to define its importance in cardiovascular health and disease."
Max ERC Funding
2 255 659 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
Project acronym CHROMIUM
Project CHROMIUM
Researcher (PI) Jennifer THOMAS
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Country United Kingdom
Call Details Advanced Grant (AdG), PE2, ERC-2015-AdG
Summary Why the Universe is void of anti-matter is one of the remaining Big Questions in Science.One explanation is provided within the Standard Model by violation of Charge Parity (CP) symmetry, producing differences between the behavior of particles and their anti-particles.CP violation in the neutrino sector could allow a mechanism by which the matter-anti matter asymmetry arose.The objective of this proposal is to enable a step change in our sensitivity to CP violation in the neutrino sector. I have pioneered the concepts and led the deployment of a small prototype using a novel approach which could eventually lead to the construction of a revolutionary Mega-ton scale Water Cherenkov (WC) neutrino detector.The goal of my research program is to demonstrate the feasibility of this approach via the construction of an intermediate sized prototype with an expandable fiducial mass of up to 10-20kt. It will use a low-cost and lightweight structure, filled with purified water and submerged for mechanical strength and cosmic ray shielding in a 60m deep flooded mine pit in the path of Fermilab’s NuMI neutrino beam in N. Minnesota.The European contribution to this experiment will be profound and definitive.Applying the idea of fast timing and good position resolution of small photodetectors, already pioneered in Europe, in place of large-area photodetector, we will revolutionize WC design.The game-changing nature of this philosophy will be demonstrated via the proof of the detector construction and the observation of electron neutrino events form the NuMI beam.The successful completion of this R&D program will demonstrate a factor of up to 100 decrease in cost compared to conventional detectors and the proof that precision neutrino measurements could be made inside a few years rather than the presently needed decades.
The project describes a five year program of work amounting to a total funding request of €3.5M, including an extra €1M of equipment funds.
Summary
Why the Universe is void of anti-matter is one of the remaining Big Questions in Science.One explanation is provided within the Standard Model by violation of Charge Parity (CP) symmetry, producing differences between the behavior of particles and their anti-particles.CP violation in the neutrino sector could allow a mechanism by which the matter-anti matter asymmetry arose.The objective of this proposal is to enable a step change in our sensitivity to CP violation in the neutrino sector. I have pioneered the concepts and led the deployment of a small prototype using a novel approach which could eventually lead to the construction of a revolutionary Mega-ton scale Water Cherenkov (WC) neutrino detector.The goal of my research program is to demonstrate the feasibility of this approach via the construction of an intermediate sized prototype with an expandable fiducial mass of up to 10-20kt. It will use a low-cost and lightweight structure, filled with purified water and submerged for mechanical strength and cosmic ray shielding in a 60m deep flooded mine pit in the path of Fermilab’s NuMI neutrino beam in N. Minnesota.The European contribution to this experiment will be profound and definitive.Applying the idea of fast timing and good position resolution of small photodetectors, already pioneered in Europe, in place of large-area photodetector, we will revolutionize WC design.The game-changing nature of this philosophy will be demonstrated via the proof of the detector construction and the observation of electron neutrino events form the NuMI beam.The successful completion of this R&D program will demonstrate a factor of up to 100 decrease in cost compared to conventional detectors and the proof that precision neutrino measurements could be made inside a few years rather than the presently needed decades.
The project describes a five year program of work amounting to a total funding request of €3.5M, including an extra €1M of equipment funds.
Max ERC Funding
3 500 000 €
Duration
Start date: 2016-10-01, End date: 2022-09-30
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
