Project acronym BAYES-KNOWLEDGE
Project Effective Bayesian Modelling with Knowledge before Data
Researcher (PI) Norman Fenton
Host Institution (HI) QUEEN MARY UNIVERSITY OF LONDON
Country United Kingdom
Call Details Advanced Grant (AdG), PE6, ERC-2013-ADG
Summary This project aims to improve evidence-based decision-making. What makes it radical is that it plans to do this in situations (common for critical risk assessment problems) where there is little or even no data, and hence where traditional statistics cannot be used. To address this problem Bayesian analysis, which enables domain experts to supplement observed data with subjective probabilities, is normally used. As real-world problems typically involve multiple uncertain variables, Bayesian analysis is extended using a technique called Bayesian networks (BNs). But, despite many great benefits, BNs have been under-exploited, especially in areas where they offer the greatest potential for improvements (law, medicine and systems engineering). This is mainly because of widespread resistance to relying on subjective knowledge. To address this problem much current research assumes sufficient data are available to make the expert’s input minimal or even redundant; with such data it may be possible to ‘learn’ the underlying BN model. But this approach offers nothing when there is limited or no data. Even when ‘big’ data are available the resulting models may be superficially objective but fundamentally flawed as they fail to capture the underlying causal structure that only expert knowledge can provide.
Our solution is to develop a method to systemize the way expert driven causal BN models can be built and used effectively either in the absence of data or as a means of determining what future data is really required. The method involves a new way of framing problems and extensions to BN theory, notation and tools. Working with relevant domain experts, along with cognitive psychologists, our methods will be developed and tested experimentally on real-world critical decision-problems in medicine, law, forensics, and transport. As the work complements current data-driven approaches, it will lead to improved BN modelling both when there is extensive data as well as none.
Summary
This project aims to improve evidence-based decision-making. What makes it radical is that it plans to do this in situations (common for critical risk assessment problems) where there is little or even no data, and hence where traditional statistics cannot be used. To address this problem Bayesian analysis, which enables domain experts to supplement observed data with subjective probabilities, is normally used. As real-world problems typically involve multiple uncertain variables, Bayesian analysis is extended using a technique called Bayesian networks (BNs). But, despite many great benefits, BNs have been under-exploited, especially in areas where they offer the greatest potential for improvements (law, medicine and systems engineering). This is mainly because of widespread resistance to relying on subjective knowledge. To address this problem much current research assumes sufficient data are available to make the expert’s input minimal or even redundant; with such data it may be possible to ‘learn’ the underlying BN model. But this approach offers nothing when there is limited or no data. Even when ‘big’ data are available the resulting models may be superficially objective but fundamentally flawed as they fail to capture the underlying causal structure that only expert knowledge can provide.
Our solution is to develop a method to systemize the way expert driven causal BN models can be built and used effectively either in the absence of data or as a means of determining what future data is really required. The method involves a new way of framing problems and extensions to BN theory, notation and tools. Working with relevant domain experts, along with cognitive psychologists, our methods will be developed and tested experimentally on real-world critical decision-problems in medicine, law, forensics, and transport. As the work complements current data-driven approaches, it will lead to improved BN modelling both when there is extensive data as well as none.
Max ERC Funding
1 572 562 €
Duration
Start date: 2014-04-01, End date: 2018-03-31
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 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 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 DENDRITECIRCUITS
Project The origins of dendritic computation within mammalian neural circuits
Researcher (PI) Michael HAUSSER
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Country United Kingdom
Call Details Advanced Grant (AdG), LS5, ERC-2015-AdG
Summary This proposal aims to address a simple question: what is the fundamental unit of computation in the brain? Answering this question is crucial not only for understanding how the brain works, but also if we are to build accurate models of brain function, which require abstraction based on identification of the essential elements for carrying out computations relevant to behaviour. In this proposal, we will build on recent work demonstrating that dendrites are highly electrically excitable to test the possibility that single dendritic branches may act as individual computational units during behaviour, challenging the classical view that the neuron is the fundamental unit of computation. We will address this question using a combination of electrophysiolgical, anatomical, imaging, molecular, and modeling approaches to probe dendritic integration in pyramidal cells and Purkinje cells in mouse cortex and cerebellum.
We will first define the computational rules for integration of synaptic input in single and multiple dendrites by examining the somatic and dendritic responses to different spatiotemporal patterns of excitatory and inhibitory inputs in brain slices. Next, we will determine how these rules are engaged by patterns of sensory stimulation in vivo, by using various strategies to map the spatiotemporal patterns of synaptic inputs onto single dendrites. To understand how physiological patterns of activity in the circuit engage these dendritic computations, we will use anatomical approaches to map the wiring diagram of synaptic inputs to individual dendrites. Finally, we will perturb the dendritic computational rules by manipulating dendritic function using molecular and optogenetic tools, in order to provide causal links between specific dendritic computations and sensory processing relevant to behaviour.
These experiments will provide us with deeper insights into how single neurons act as computing devices.
Summary
This proposal aims to address a simple question: what is the fundamental unit of computation in the brain? Answering this question is crucial not only for understanding how the brain works, but also if we are to build accurate models of brain function, which require abstraction based on identification of the essential elements for carrying out computations relevant to behaviour. In this proposal, we will build on recent work demonstrating that dendrites are highly electrically excitable to test the possibility that single dendritic branches may act as individual computational units during behaviour, challenging the classical view that the neuron is the fundamental unit of computation. We will address this question using a combination of electrophysiolgical, anatomical, imaging, molecular, and modeling approaches to probe dendritic integration in pyramidal cells and Purkinje cells in mouse cortex and cerebellum.
We will first define the computational rules for integration of synaptic input in single and multiple dendrites by examining the somatic and dendritic responses to different spatiotemporal patterns of excitatory and inhibitory inputs in brain slices. Next, we will determine how these rules are engaged by patterns of sensory stimulation in vivo, by using various strategies to map the spatiotemporal patterns of synaptic inputs onto single dendrites. To understand how physiological patterns of activity in the circuit engage these dendritic computations, we will use anatomical approaches to map the wiring diagram of synaptic inputs to individual dendrites. Finally, we will perturb the dendritic computational rules by manipulating dendritic function using molecular and optogenetic tools, in order to provide causal links between specific dendritic computations and sensory processing relevant to behaviour.
These experiments will provide us with deeper insights into how single neurons act as computing devices.
Max ERC Funding
2 495 563 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym DEVOCHROMO
Project Chromosome structure and genome organization in early mammalian development
Researcher (PI) Peter Fraser
Host Institution (HI) THE BABRAHAM INSTITUTE
Country United Kingdom
Call Details Advanced Grant (AdG), LS2, ERC-2013-ADG
Summary "The spatial organization of the genome inside the cell nucleus is tissue-specific and has been linked to several nuclear processes including gene activation, gene silencing, genomic imprinting, gene co-regulation, genome maintenance, DNA replication, DNA repair, chromosomal translocations and X chromosome inactivation. In fact, just about any nuclear/genome function has a spatial component that has been implicated in its control. We know surprisingly little about chromosome conformation and spatial organization or how they are established. The extent to which they are a cause or consequence of genome functions are current topics of considerable debate, however emerging data from my group and many other groups world-wide indicate that nuclear location and organization are drivers of genome functions, which in cooperation with other features including epigenetic marks, non-coding RNAs and trans-factor binding bring about genome control. Thus, genome spatial organization can be considered on a par with other epigenetic features that together contribute to overall genome control. The classical paradigm of early mammalian development arguably represents the most dramatic and yet least understood process of genome reprogramming, where a single cell undergoes a series of divisions to ultimately give rise to the hundreds of different cell types found in a mature organism. Study of pre-implantation embryo development is hindered by the very nature of the life form, composed of extremely low cell numbers at each stage, which severely limits the options for investigation. My lab has recently developed a novel technique called single cell Hi-C, which has the power to detect tens of thousands of simultaneous chromatin contacts from a single cell. In this application I propose to apply this technology to study chromosome structure and genome organization during mouse pre-implantation development along with single cell transcriptome analyses from the same cells."
Summary
"The spatial organization of the genome inside the cell nucleus is tissue-specific and has been linked to several nuclear processes including gene activation, gene silencing, genomic imprinting, gene co-regulation, genome maintenance, DNA replication, DNA repair, chromosomal translocations and X chromosome inactivation. In fact, just about any nuclear/genome function has a spatial component that has been implicated in its control. We know surprisingly little about chromosome conformation and spatial organization or how they are established. The extent to which they are a cause or consequence of genome functions are current topics of considerable debate, however emerging data from my group and many other groups world-wide indicate that nuclear location and organization are drivers of genome functions, which in cooperation with other features including epigenetic marks, non-coding RNAs and trans-factor binding bring about genome control. Thus, genome spatial organization can be considered on a par with other epigenetic features that together contribute to overall genome control. The classical paradigm of early mammalian development arguably represents the most dramatic and yet least understood process of genome reprogramming, where a single cell undergoes a series of divisions to ultimately give rise to the hundreds of different cell types found in a mature organism. Study of pre-implantation embryo development is hindered by the very nature of the life form, composed of extremely low cell numbers at each stage, which severely limits the options for investigation. My lab has recently developed a novel technique called single cell Hi-C, which has the power to detect tens of thousands of simultaneous chromatin contacts from a single cell. In this application I propose to apply this technology to study chromosome structure and genome organization during mouse pre-implantation development along with single cell transcriptome analyses from the same cells."
Max ERC Funding
2 401 393 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym DISCSIM
Project Hydrodynamical simulations of protoplanetary discs in the era of ALMA imaging
Researcher (PI) Catherine Clarke
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Advanced Grant (AdG), PE9, ERC-2013-ADG
Summary "This is a proposal for an ambitious programme of state of the art hydrodynamical simulations, designed to answer some key questions about the role of disc self-gravity in planet formation. The programme is also designed so as to maximize the synergy with the new observational constraints from high resolution imaging data from the Atacama Large Millimetre Array that will become available over the timescale of the grant. The five year programme should provide definitive answers about whether planet formation is able to get going during the early, self-gravitating phase of disc evolution and how, if so, it would affect the further evolution of the disc. The topic of gravitational disc fragmentation as a route to planet formation is currently in a state of crisis, with recent simulations undermining what had become a consensus view on the subject. A dedicated and carefully constructed approach, as detailed here, is required to solve this problem."
Summary
"This is a proposal for an ambitious programme of state of the art hydrodynamical simulations, designed to answer some key questions about the role of disc self-gravity in planet formation. The programme is also designed so as to maximize the synergy with the new observational constraints from high resolution imaging data from the Atacama Large Millimetre Array that will become available over the timescale of the grant. The five year programme should provide definitive answers about whether planet formation is able to get going during the early, self-gravitating phase of disc evolution and how, if so, it would affect the further evolution of the disc. The topic of gravitational disc fragmentation as a route to planet formation is currently in a state of crisis, with recent simulations undermining what had become a consensus view on the subject. A dedicated and carefully constructed approach, as detailed here, is required to solve this problem."
Max ERC Funding
1 892 844 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym EMPSI
Project Receptors, Channels and Transporters:
Development and Application of Novel Technologies for Structure Determination
Researcher (PI) Christopher Gordon Tate
Host Institution (HI) MEDICAL RESEARCH COUNCIL
Country United Kingdom
Call Details Advanced Grant (AdG), LS1, ERC-2013-ADG
Summary Structure determination of G protein-coupled receptors (GPCRs) has been exceedingly successful over the last 5 years due to the development of complimentary generic methodologies that will now allow the structure determination of virtually any GPCR. However, these technologies address only two aspects of the process, namely the stability of the receptors during purification and the ability to form well-diffracting crystals. The strategies also apply only to GPCRs and not transporters or ion channels. The recent successes have been of GPCRs that are expressed in either yeasts or in insect cells using the baculovirus expression system, but many membrane proteins are expressed poorly in these systems or may be expressed in a misfolded non-functional form. A second issue with the future structure determination of GPCRs is the lack of generic technologies to allow the crystallisation of arrestin-GPCR and G protein-GPCR complexes. Although one G protein GPCR complex has been crystallised this was exceedingly diffciult and resulted in poor resolution of the GPCR component of the complex. We believe that it is possible to thermostabilise both arrestin and heterotrimeric G proteins, which will allow a simplified strategy for the crystallisation and structure determination of GPCR complexes. This is based on the development of the strategy of conformational thermostabilisation of GPCRs developed in our lab that has resulted in the structure determination of 3 different GPCRs bound to either antagonists, partial agonists, full agonists and/or biased agonists.
The aims are:
1. The development of generic methodology for the production of eukaryotic membrane proteins in mammalian cells.
2. The development of a thermostable functional arrestin mutant
3. Structures of β1-adrenoceptor, adenosine A2A receptor and angiotensin receptor bound to a G protein and arrestin
4. Understanding the role of each amino acid residue in the activation process of GPCRs through saturation mutagenes
Summary
Structure determination of G protein-coupled receptors (GPCRs) has been exceedingly successful over the last 5 years due to the development of complimentary generic methodologies that will now allow the structure determination of virtually any GPCR. However, these technologies address only two aspects of the process, namely the stability of the receptors during purification and the ability to form well-diffracting crystals. The strategies also apply only to GPCRs and not transporters or ion channels. The recent successes have been of GPCRs that are expressed in either yeasts or in insect cells using the baculovirus expression system, but many membrane proteins are expressed poorly in these systems or may be expressed in a misfolded non-functional form. A second issue with the future structure determination of GPCRs is the lack of generic technologies to allow the crystallisation of arrestin-GPCR and G protein-GPCR complexes. Although one G protein GPCR complex has been crystallised this was exceedingly diffciult and resulted in poor resolution of the GPCR component of the complex. We believe that it is possible to thermostabilise both arrestin and heterotrimeric G proteins, which will allow a simplified strategy for the crystallisation and structure determination of GPCR complexes. This is based on the development of the strategy of conformational thermostabilisation of GPCRs developed in our lab that has resulted in the structure determination of 3 different GPCRs bound to either antagonists, partial agonists, full agonists and/or biased agonists.
The aims are:
1. The development of generic methodology for the production of eukaryotic membrane proteins in mammalian cells.
2. The development of a thermostable functional arrestin mutant
3. Structures of β1-adrenoceptor, adenosine A2A receptor and angiotensin receptor bound to a G protein and arrestin
4. Understanding the role of each amino acid residue in the activation process of GPCRs through saturation mutagenes
Max ERC Funding
2 378 162 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
