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University of Cambridge

Results

Amount: £227,598
Funder: The Wellcome Trust
Recipient: University of Cambridge

Gene Expression Heterogeneity in the Maintenance and Coordinated Differentiation of Neuromesodermal Progenitors in vivo. 21 Oct 2015

Neuromesodermal progenitors (NMps) are a population of cells that give rise to neural and mesodermal derivatives during the elongation of the posterior body in vertebrate embryos. Despite their importance for understanding vertebrate development, we currently know little about the mechanisms that maintain these cells. Experiments measuring gene expression levels within single cells in vitro suggest the hypothesis that increased heterogeneity of neural and mesodermal markers allows for continual sampling of both these fates within NMps, and that this acts as a mechanism by which they retain the ability to give rise to both lineages. Here, I propose to perform quantitative, single-cell measurements of gene expression within whole zebrafish embryos and relating this directly to cell lineage. Finally, I shall apply a novel method for live imaging of both protein and mRNA dynamics within whole zebrafish embryos. Together, these studies will provide an unparalleled study of the role of gene expression during development and establish a strong research programme aimed at uncovering the molecular mechanisms that control this.

Amount: £840,340
Funder: The Wellcome Trust
Recipient: University of Cambridge

The modularity of action control in the nervous system. 11 Nov 2015

The first phase of the proposed research is to establish the principles by which control structures are represented in the nervous system in motor control and sequential decision-making. The behavioural patterns revealed using well-established assays will be tested in order to provide evidence for an optimally efficient representation of the task structure as predicted by the common computational framework of Bayesian structure modeling. The second phase is to use neuroimaging techniques (fMR I) on humans in order to identify the neural substrates of a learning process which efficiently encodes the task structure. Parallel analyses will be performed on a rich, and already acquired, dataset composed of electrophysiological recordings from rodents. This will test whether the same model applies across species, and critically, relate the model to previously established neural phenomenon. The results of these two phases will be integrated into a novel neuro-computational model of the a cquisition of control representations in corticostriatal circuits and their use in decision-making. Based on the hyperactivity of the dopaminergic system, the resulting model will be probed for predictions of behavioural deficits which will then be tested in patients suffering from schizophrenia.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Ischia Summer School on the History of the Life Sciences 31 Aug 2016

The Ischia Summer School on the History of the Life Sciences provides advanced training in history of biology and medicine in a historically rich and naturally beautiful setting for 26 PhD students and postdoctoral fellows, with strong UK representation. Lectures and seminars at the Ischia branch of the Naples Zoological Station by nine distinguished international faculty, with student presentations and discussions, encourage exchange of ideas across academic cultures. The 15th school, scheduled for 24 June – 1 July 2017, is on ‘Cycles of Life’, which we understand to range from ancient cycles of generation and corruption, the seasons and the weather cycle to modern reproductive, metabolic and ‘biogeochemical’ cycles, as well as contraceptive interventions in menstrual cycles and strategies to disrupt pest and pathogen life cycles. We will trace connections and identify patterns of continuity and change, explore shared properties of cycles and the differences and relations between disciplines and research programmes. The Naples Station will grant use of facilities, NSF will cover the costs of American participation and students will each pay €300. We are very grateful to Dan O'Connor for inviting an application and would be thrilled if the Trust could provide the balance of the funds.

Amount: £19,960
Funder: The Wellcome Trust
Recipient: University of Cambridge

Behaviour Change by Design: Generating and Implementing Evidence to Improve Health for All 11 Jul 2017

Reducing food, alcohol and tobacco consumption would dramatically reduce non-communicable disease and, since these behaviours cluster by deprivation, would also reduce health inequalities. However, progress in achieving such behaviour change is slow. Traditional approaches to behaviour change involve providing information with, at best, modest population-level effects and sometimes increased inequalities. Conversely, Choice Architecture interventions ("Nudges") have potentially larger, more equitable effects, involving re-designing environments e.g. reducing plate size to reduce food consumption. However, evidence of effectiveness in real-world settings and understanding of mechanisms are limited. We will bridge this knowledge gap through a novel collaboration between behavioural and cognitive sciences. In the most ambitious co-ordinated set of studies to date, we propose field studies to estimate effect sizes of promising Choice Architecture interventions to reduce food, alcohol and tobacco consumption. Enabled by unprecedented collaborations, these will be conducted in supermarkets, bars and cafeterias and interventions optimised through laboratory studies determining mechanisms. We will run international workshops, public engagement activities and a Behaviour Change Summit to facilitate implementing the evidence generated, overseen by an Implementation Advisory Panel. This will enable us to realise our vision of accelerating progress in changing behaviour by re-designing environments to improve health for all.

Amount: £3,123,724
Funder: The Wellcome Trust
Recipient: University of Cambridge

Putting genomic surveillance at the heart of viral epidemic response. 05 Apr 2017

This proposal is to develop an end-to-end system for processing samples from viral outbreaks to generate real-time epidemiological information that is interpretable and actionable by public health bodies. Fast evolving RNA viruses (such as Ebola, MERS, SARS, influenza etc) continually accumulate changes in their genomes that can be used to reconstruct the epidemiological processes that drive the epidemic. Based around a recently developed, single-molecule portable sequencing instrument, the MinION, we will create a 'lab-in-a-suitcase' that will be deployed to remote and resource-limited locations. These will be used to sequence viral genomes from infected patients which will then be uploaded to a central database for rapid analysis. We will develop methods for a wide-range of emerging viral diseases. Novel molecular biology methods will allow us to sequence individual viruses within a patient. Bioinformatics tools will be developed simple enough for non-bioinformaticians to use, without reliance on Internet connectivity. We will develop software to integrate these data and associated epidemiological knowledge to reveal the processes of transmission, virus evolution and epidemiological linkage. Finally we will develop a web-based visualization platform where the outputs of the statistical analyses can be interrogated for epidemiological insights within days of samples being taken from patients.

Amount: £482,639
Funder: The Wellcome Trust
Recipient: University of Cambridge

The metabolic regulation of hypoxia inducible transcription factors. 05 Dec 2016

We have recently identified a novel pathway for metabolic regulation of HIF1 alpha by the OGDHC1. To continue this new area of research, it is essential that we have the necessary funds to maintian our competitive edge within the field, without diverting resources from our successful ubiquitin studies. The initial research on HIFs has been conducted by a talented graduate student, Stephen Burr. The timing of this funding request is particularly important, as it will allow Stephen to transfer his skills with a sufficient overlap for a new postdoctoral researcher to pursue this project.

Amount: £127,447
Funder: The Wellcome Trust
Recipient: University of Cambridge

In vivo mechanisms of epithelial tissue morphogenesis 11 Jul 2017

Understanding how a tri-dimensional tissue is built from the genetic blueprint is a key frontier in biology. In addition to genes known to be important in specific aspects of morphogenesis, physical constraints and properties play a major role in building tissues. In this proposal, I aim to understand how the genetic inputs integrate with the mechanical properties of the cells and tissues to produce form. To investigate this, we study the early development of the Drosophila embryo. We have found previously that actomyosin-rich boundaries play an important role in two fundamental and conserved morphogenetic phenomena, axis extension and compartmental boundary formation. We have also found that an extrinsic force contributes to axis extension. We will build on these findings by first investigating how the actomyosin-rich boundaries form and how they might repair genetic patterns during axis extension. Second, we will ask how, during compartmentalisation, they control the planar orientation of cell division and also epithelial folding. Finally, we will examine the impact of actomyosin-rich boundaries and extrinsic forces on epithelial tissue mechanics. Our approaches will be interdisciplinary, combining genetic, quantitative and in silico analyses to find novel and universal morphogenetic rules.

Amount: £1,440,082
Funder: The Wellcome Trust
Recipient: University of Cambridge

The cognitive neuroscience of over-eating: normative and clinical studies of goal-driven and stimulus-driven responses 05 Apr 2017

There is a pressing need to understand the phenotypic variations of obesity in order to elucidate the diverse pathways and mechanisms by which it arises and, ultimately, to offer suitably tailored interventions. My proposed work aims to provide insights into the cognitive neuroscience of health-harming over-consumption. Its ultimate goals are to characterise cognitive mechanisms underlying eating behaviours, exploring how these are selected and deployed in ways that are shaped by both internal and environmental signals. The work is based on the view that obesity is ultimately driven by a complex integration of environmental and bodily signals and that a comprehensive approach must characterise this integration in order to determine how it may be altered in over-eating. My proposal has the following goals: To understand how stimulus-driven (automatic) and goal-directed (reflective) reward behaviours are balanced in relation to eating choices and to explore how this balance may differ across hungry and sated, lean and obese people. To relate these underlying processes to hormonal/metabolic signals as well and to real-world eating choices. To characterise the effects of three specific perturbations to this integrated system: (i) elective gastrectomy, (ii) single gene mutations affecting hypothalamic circuitry and (iii) psychopharmacological manipulations

Amount: £1,500,053
Funder: The Wellcome Trust
Recipient: University of Cambridge

Adaptive decision templates in the human brain 30 Nov 2016

Interacting with the surrounding environment depends on our ability to extract meaningful patterns from incoming streams of sensory information. Learning and experience are known to facilitate this skill; yet, we know little about how the brain extracts structure and generalises this knowledge to novel settings. Here, I propose to test the brain mechanisms underlying structure learning using contrasting tasks that involve learning structure in space vs. time at different levels of complexity (simple vs. complex feature contingencies). I will use computational modelling to interrogate the processes involved in learning behaviourally-relevant structures (i.e. decision templates). I will relate this system-level insight to multimodal neuroimaging to provide converging evidence for brain mechanisms that mediate learning specialisation and generalisation. I will exploit high-field imaging to test fine-scale decision templates in the visual cortex. I will combine 7T imaging with human electrophysiology (MEG/EEG) and interventions (TMS) to test for local and larger-scale brain circuits that retune decision templates through feedback and inhibitory interactions. Finally, I will test whether these mechanisms support our ability to generalise previous experience to novel contexts and tasks. This integrated approach will advance our understanding of the brain’s capacity for adaptive and resilient behaviour with implications for promoting lifelong learning.

Amount: £1,344,200
Funder: The Wellcome Trust
Recipient: University of Cambridge

Developmental mechanisms 30 Sep 2017

Not available

Amount: £2,750,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Development and leptin signalling in human stem cell-derived POMC neurons 31 Jan 2017

Energy homeostasis in mammals is tightly controlled by a distinct neural circuit in the hypothalamus and its dysfunction leads to obesity. Pro-opiomelanocortin (POMC) neurons are a central component of this circuit. While obesity research has been largely limited to studies in rodents in the past decades, recently published protocols now allow the in vitro generation of human POMC neurons from human pluripotent stem cells (hPSCs). This enables us to study disease-associated mechanisms directly in the human cell type relevant to obesity. In my PhD I will contribute to a thorough characterisation and optimisation of this in vitro system. I will study when human POMC neurons are born in culture, assess their responsiveness to metabolic cues that regulate their activity and test different means of enhancing this responsiveness. This in vitro characterisation of POMC neuronal activity will be complemented by transplantation studies, in which I will test whether hPSC-derived POMC neurons possess all the features of functional maturity required to reinstall energy homeostasis in obese mice. I will finally use this novel tool to study the molecular mechanisms of certain signalling pathways in human POMC neurons, which might lead to the identification of potential targets for therapeutic intervention in human obesity.

Amount: £46,168
Funder: The Wellcome Trust
Recipient: University of Cambridge

The molecular basis of KAP1-dependent transcriptional silencing 31 Jan 2017

The transcriptional regulator KRAB-associated protein 1 (KAP1) is crucial for preserving genome integrity by repressing potentially harmful retroelements. Following its recruitment to retrotransposons by KRAB domain containing zinc finger proteins (KRAB-ZFPs), KAP1 coordinates the assembly of a repressor complex containing the histone methyltransferase SETDB1 and histone deacetylase 1 (HDAC1) to induce epigenetic silencing of these elements. In addition to its role in repressing transposons, KAP1 also regulates the expression levels of numerous other genes. Interestingly, the transcriptional activities of KAP1 can be strongly influenced by posttranslational modifications (PTMs). Most notably, phosphorylation at S473 and phosphorylation at S824 both significantly alleviate the repression mediated by KAP1. The molecular mechanisms underlying these processes, however, remain poorly understood. To elucidate the structural basis of KAP1-dependent transcriptional repression, we will reconstitute a complex consisting of KAP1, SETDB1, the KRAB-ZFP ZNF93 and a DNA fragment containing the recognition sequence for ZNF93. Subsequently, we use single-particle cryo-EM to determine the structure of this complex. In addition, we will investigate the mechanism by which PTMs regulate the transcriptional activities of KAP1. Our central objective in this context will be determining how phosphorylation at S473 or S824 results in transcriptional activation.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Fundamental mechanisms controlling human energy homeostasis 11 Jul 2017

Obesity and associated diseases such as type 2 diabetes, cardiovascular disease and some cancers represent a significant health burden. My overall aim is to identify new therapeutic strategies for severe obesity. Using extensive genetic and clinical data on unique cohorts of individuals at both extremes of the weight distribution (severe obesity and thinness), we will comprehensively map the molecular networks that maintain energy homeostasis and their disruption in disorders of weight regulation. Building on our previous work, we will focus on dissecting cellular mechanisms that converge on leptin-melanocortin signalling using human stem-cell derived hypothalamic neurons. In human studies, we will characterise the effects of specific pathways on eating behaviour, energy expenditure and substrate utilisation. By uncovering the fundamental mechanisms that control human energy homeostasis, our goal is to identify and validate control points that can be targeted to improve outcomes in obesity associated diseases.

Amount: £3,582,289
Funder: The Wellcome Trust
Recipient: University of Cambridge

Neuronal reward mechanisms 30 Nov 2016

We investigate neuronal reward and economic decision signals in behavioural tasks with designs from learning and economic decision theories, supplemented by selected, closely related neuroimaging experiments. We study the main components of the brain's reward system, including dopamine neurons (reward prediction error), orbitofrontal cortex (economic decision variables), striatum (so far insufficiently characterised reward signals) and amygdala (short- and long-term rewards). We search for reward and decision signals that provide explanations and hardware implementations for the constructs of reward and economic theories. We need to know these fundamental neuronal signals before focussing on cellular and molecular mechanisms, which differs from work on sensory and motor systems whose signals are better characterised.  We state three aims:  Aim 1: We characterise neuronal processing of skewness-risk, arguably the most frequent risk form.  Aim 2: We identify neuronal signals for utility and test formal axioms for utility maximisation, which is supposedly the goal of 'rational' agents. Utility is THE basic economic decision variable that explains most economic choices.  Aim 3: We assess neuronal representations of preferences, and bridge the gap between biologically necessary rewards and tradable economic goods, by testing basic assumptions of revealed preference theory.

Amount: £4,413,529
Funder: The Wellcome Trust
Recipient: University of Cambridge

Fundamental mechanisms controlling human energy homeostasis 11 Jul 2017

Obesity and associated diseases such as type 2 diabetes, cardiovascular disease and some cancers represent a significant health burden. My overall aim is to identify new therapeutic strategies for severe obesity. Using extensive genetic and clinical data on unique cohorts of individuals at both extremes of the weight distribution (severe obesity and thinness), we will comprehensively map the molecular networks that maintain energy homeostasis and their disruption in disorders of weight regulation. Building on our previous work, we will focus on dissecting cellular mechanisms that converge on leptin-melanocortin signalling using human stem-cell derived hypothalamic neurons. In human studies, we will characterise the effects of specific pathways on eating behaviour, energy expenditure and substrate utilisation. By uncovering the fundamental mechanisms that control human energy homeostasis, our goal is to identify and validate control points that can be targeted to improve outcomes in obesity associated diseases.

Amount: £50,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Embryo architecture, potency and tissue interactions during mouse and human development 11 Jul 2017

Mammalian embryogenesis entails close partnership between embryonic and extra-embryonic tissues to regulate changes in embryo architecture and developmental potency. We aim for an integrated view of how these events progress hand in hand during key stages of mouse and human embryogenesis. The first architectural changes of the embryo are polarisation and compaction that trigger the separation of embryonic and extra-embryonic lineages. Yet their own trigger remains unknown. We will dissect potential triggering pathways and through genetic manipulations determine their importance for cell fate. Embryo remodelling at implantation is intimately associated with pluripotent-state transitions. We will harness our novel techniques for embryo culture throughout implantation to uncover mechanisms behind these events in relation to signalling partnerships between embryonic and extra-embryonic tissues. By arranging partnership between embryonic and extra-embryonic stem cells in 3D-culture we have recapitulated embryo-like morphogenesis and spatio-temporal gene-expression. We will characterise tissue interactions in such stem cell-derived embryos to understand principles of self-organisation. Our work established an unprecedented opportunity to study human early post-implantation embryogenesis in-vitro. We will build the first morphological and transcriptional atlas of human development beyond implantation. This will bring understanding of normal development and shed light upon why many pregnancies fail at early stages.

Amount: £2,135,983
Funder: The Wellcome Trust
Recipient: University of Cambridge

Contextual determinants of surprise in health, development and disorder. 31 May 2017

The goal of this research proposal is to build a theoretical and experimental framework to understand the contextual determinants of "surprise" (expectation violations/prediction errors) in health, development, and disorder. I have the following three aims: 1) To exploit high-field neuroimaging and pharmacological manipulations in healthy adults to reveal the precise neural mechanisms that alter surprise processing in response to volatility, and validate different pupil metrics as a window into central neuromodulatory function. 2) To conduct model-based neuroimaging in infants, for the first time, to predict risk for the dimensional symptoms of autism, and reveal the computational neurodevelopment of probabilistic and volatility learning in infants. 3) To develop a unified computational framework of surprise-driven learning that has the specificity to reveal separable mechanisms of psychopathology in different neuropsychiatric conditions and the potential to be used as a clinical tool. To achieve these objectives I will utilise the same cognitive tasks, pupillometric measurements and computational models of learning across three research themes. This ensures that while the individual projects are strongly hypothesis-driven the findings can be directly translated across developmental, adult, and disordered states. Key words: autism, neurodevelopment, predictive coding, surprise, computational models, 7T fMRI, pharmacology, noradrenaline, psychosis.

Amount: £983,275
Funder: The Wellcome Trust
Recipient: University of Cambridge

KRAB-ZFPs and the establishment of lineage- and species-specific gene regulatory networks 31 May 2017

KRAB-ZFPs constitute a large yet neglected family of proteins with around 350 members in human and mouse. Collectively, they target transposable elements and until recently were thought to be mostly involved in their transcriptional repression in embryonic stem cells. During my post-doctoral work, I unveiled the binding sites of most (222) human KRAB-ZFPs, but the role played by the majority of them could not be fully explained by current theorems. Instead, we found that many target ancient transposable elements which often contain regulatory platforms; we also obtained correlative evidence that these could affect the expression of nearby genes. We hypothesize that evolutionary conserved KRAB-ZFPs can use their heterochromatin-inducing capabilities to modify accessibility of these transposable element-derived regulatory elements. We propose to functionally demonstrate this potential by using large scale enhancer screens in multiple cell types. Furthermore, we want to follow-up on these findings by genetic manipulations aimed at characterizing the biological processes affected by a few KRAB-ZFPs, including the generation of mouse models. Finally, we want to better understand the evolution dynamics of KRAB-ZFP binding sites and verify if they can lead to lineage- and species-specific rewiring of gene regulatory networks.

Amount: £1,393,506
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding the role of the viral polymerase in influenza virus virulence 31 May 2017

The development of novel strategies against influenza viruses depends on our understanding of influenza virus replication and pathogenicity. The former largely depends on the activity of the viral RNA polymerase, which copies and transcribes the viral genome, while the latter is multifaceted and influenced by both viral and host factors. Interestingly, recent findings show that the RNA polymerases of highly pathogenic influenza A viruses produce short RNAs, or mini viral RNAs (mvRNAs), which are non-contiguous in the viral genome and strong inducers of the interferon response. Because they are not made by RNA polymerases of seasonal influenza strains, mvRNA synthesis may be a transformational advance in our understanding of the ‘cytokine storm’ that underlies the pathogenicity of virulent influenza viruses. Unfortunately, our basic understanding of the influenza RNA polymerase is limited and it is unclear how the mvRNAs are made. I here plan to use single-molecule FRET, deep-sequencing and structure-guided mutagenesis to advance our basic understanding of influenza virus RNA synthesis, focussing on the molecular mechanics behind i) influenza transcription initiation, ii) the differences between the RNA polymerases of highly pathogenic and seasonal influenza strains, and iii) the action of influenza inhibitors that target the RNA polymerase.

Amount: £922,885
Funder: The Wellcome Trust
Recipient: University of Cambridge