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University of Cambridge

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Cambridge Stem Cell Institute 30 Oct 2016

Stem and progenitor cells are essential for the maintenance of metazoan tissues. Their dysfunction underlies diverse human diseases and their manipulation provides enormous therapeutic possibilities. The Cambridge Stem Cell Institute (CSCI) is a world-leading centre for stem cell research. Its mission is to transform the prevention, diagnosis and treatment of disease through a deep understanding of the mechanisms regulating stem and progenitor cells, both normal and pathological. In 2018 CSCI investigators will come together in a new purpose-built building on the Cambridge Biomedical Campus adjacent to Addenbrookes Hospital. A key strategy is to embed biological, clinical and physical scientists operating across disparate tissues and at multiple scales, thus allowing commonalities and differences to be explored in an cohesive and inter-disciplinary manner. A network of affiliated PIs will provide bridges to basic and disease-focused institutes throughout Cambridge and will ensure that CSCI represents the heart of a vibrant stem cell community. Importantly a critical mass of clinician scientists will create synergistic interactions between basic scientists and those driven by disease-focused questions, thus ensuring that CSCI is fully integrated with its clinical environment and empowered to pursue its translational goals.

Amount: £9,793,833
Funder: The Wellcome Trust
Recipient: University of Cambridge

Socio-cultural factors in Zika virus outcomes in Lusophone African countries 30 Sep 2016

What is the research question?1) What social barriers to, and enablers for, effective public health responses/adoption ofpreventive measures can be identified in health beliefs and practices associated withthe Zika virus, with particular attention to variations between countries with differentincidence of the disease, socio-demographic groups, and over time? ( WT-DFIDChallenge One)2) What are the affordances and limitations in the context of epidemics for this method ofdynamic social data analysis and health communications/monitoring amonghard-to-reach populations, and how can it contribute to the rapid dissemination ofinformation and knowledge in mitigating future epidemics? ( WT-DFID ChallengeThree)

Amount: £123,126
Funder: The Wellcome Trust
Recipient: University of Cambridge

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £3,000,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Diagnostically cross-cutting intermediate phenotypes of impulsivity and compulsivity. 19 Nov 2015

The proposed research will deconstruct impulsivity and compulsivity using cutting-edge neurocognitive tests, structural and functional neuroimaging, pharmacological challenge of the brain dopamine/adenosine systems, and quantification of peripheral dopamine status. In this way I aim to link cognitive and brain systems phenotypes of impulsivity/compulsivity to more mechanistically specific markers of abnormal neurotransmission and to demonstrate how these intermediate phenotypes are expressed dim ensionally in the population, and cut across two major diagnostic categories of psychiatric disorder. The key goals will be to address three core hypotheses: 1. That underlying intermediate phenotypes of impulsivity/compulsivity (measured using neurocognitive tests and psychopathology questionnaires) manifest as extremes of the normal population distribution (in the absence of overt psychiatric disorders) and, similarly, in classical psychiatric disorders of impulsivity and compulsivity (atte ntion-deficit hyperactivity disorder and obsessive-compulsive disorder). 2. That these intermediate phenotypes of impulsivity/compulsivity emerge as a consequence of altered fronto-striatal activity, and are under the modulatory influence of brain dopaminergic and adenosine neurochemical systems. 3. That these intermediate phenotypes of impulsivity/compulsivity, and their tractability to dopaminergic and adenosine drug manipulations, are correlated with peripheral blood-based biomarkers o f dopamine function.

Amount: £989,383
Funder: The Wellcome Trust
Recipient: University of Cambridge

An electron cryo-microscopy resource for macromolecular structure determination in the University of Cambridge 16 Jun 2016

We seek to establish an advanced electron cryo-microscopy (cryo-EM) facility dedicated to structural studies of biological macromolecular assemblies. The facility would provide a revolutionary new tool to the large structural biology community in the University that would enable acquisition of critical data in support of a wide and diverse range of projects tackling fundamental problems in molecular biology relevant to human health. Currently, the named applicants primarily use X-ray crystallography to study large assemblies, but many of these samples cannot be readily crystallised. The recent development of a new generation of direct electron detectors, together with sophisticated data-processing software, has dramatically improved cryo-EM analysis, which now achieves routinely sub-nanometer resolution. However, we lack access to such a facility in the University. A wide range of projects will benefit from the proposed facility, including studies of multi-drug efflux membrane transporters; assemblies of RNA metabolism; complexes regulating chromatin structure, DNA replication and repair; mitochondrial complex I and its roles in human disease; ribosome assembly defects in bone marrow failure; presenilin complexes and other assemblies related to neurodegeneration; human neurotransmitter transporters and G-protein coupled receptors; transport vesicle and organelle biogenesis; molecular mechanism of ATP synthase; and methods development in EM of biological macromolecules.

Amount: £1,000,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge - Infection, Immunity and Inflammation 30 Sep 2016

Cambridge - Infection, Immunity and Inflammation

Amount: £133,716
Funder: The Wellcome Trust
Recipient: University of Cambridge

University of Cambridge - Metabolic and Cardiovascular Disease 30 Sep 2016

University of Cambridge - Metabolic and Cardiovascular Disease

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge - Infection, Immunity and Inflammation 30 Sep 2016

Cambridge - Infection, Immunity and Inflammation

Amount: £133,716
Funder: The Wellcome Trust
Recipient: University of Cambridge

University of Cambridge - Developmental Mechanisms 30 Sep 2016

University of Cambridge 4 year PhD Programme - Developmental Mechanisms

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the influence and therapeutic potential of RNA Gquadruplex structures on positive 30 Sep 2016

An!increasing!body!of!evidence!suggests!that!RNA!secondary!structures,!such!as!G] quadruplexes!and!stem]loops,!play!crucial!roles!in!the!regulation!of!translation!and!RNA! replication!during!viral!infection.!Our!ability!to!exploit!such!RNA!structures!therapeutically!is! dependent!upon!our!knowledge!of!how!they!act,!which!remains!unclear.!!One!goal!of!this! research!is!to!systematically!identify!and!examine!the!influence!of!RNA!G]quadruplexes! present!in!the!coding!regions!of!two!widely!used!model!calciviruses.!Using!the!established! reverse!genetic!systems!for!these!viruses,!the!effects!of!mutations!that!alter!the!presence!and! distribution!of!G]quadruplex!structures!can!be!studied,!both!in!terms!of!virus!efficiency!and!rate! of!RNA!synthesis!in!cell!culture.!If!suitable!mutated!viruses!are!obtained,!the!persistence!of! these!viruses!within!a!small!animal!model!will!be!examined!which!will!give!insights!into!the! suitability!of!such!modified!viruses!for!use!as!vaccines.!The!second!goal!of!this!research!is!to! investigate!the!mechanisms!by!which!helicases!control!the!regulation!imposed!by!such!RNA! structures.!Using!a!reconstitution!system!for!translation!initiation!in&vitro,!the!hierarchy!between! different!RNA!secondary!structures!and!the!helicases!that!mediate!their!unwinding!can!be! examined.

Amount: £4,930
Funder: The Wellcome Trust
Recipient: University of Cambridge

An Interdisciplinary Investigation into Carolingian Medical Knowledge and Practice 10 May 2016

Focusing on the late eighth and ninth centuries, I am proposing an interdisciplinary project that aims to present a more comprehensive picture of Carolingian health and medicine than previous research has offered. I shall investigate early medieval medical knowledge and explore the question of its possible application through an in-depth analysis of textual sources supplemented by the skeletal record. Medical manuscripts shed light on the medical knowledge circulating among the literate elite, illustrating the perceptions of medicine within ecclesiastical communities, the movement of texts, and the adaptation and incorporation of classical learning in a Christian, medieval world. A review of the skeletal remains from cemeteries around the Frankish Empire during this period will provide insights into the health and lived experiences of people from all walks of life – including the vast majority of the population unrecorded by the texts. I shall compare the medical knowledge contained in the manuscripts with the palaeopathological and osteological record captured by the bones, asking: is there evidence that this knowledge was potentially applied? I hope to assess whether different types of communities and texts yield different answers. This interdisciplinary approach takes the study of Carolingian health and medicine in a new direction.

Amount: £94,637
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the phenotype, function and interactions of tissue-resident B cells 30 Sep 2016

Tissue-specific immunity is shaped by the local milieu. In organ systems that interface with the environment (e.g. skin, gastrointestinal tract), exogenous signals generated by commensals or diet can profoundly influence resident immune cells. In non-interfacing tissues (e.g. kidney), endogenous signals such as interstitial osmolality may also influence the immune landscape. Tissue epithelial cells play an important role as environmental sensors and may instruct local immune responses. In addition, environmental cues may be directly detected by resident immune cells. To date, studies of tissue sentinels have focused on innate immune cells and on T cells with limited data on B cells. We have preliminary data from human and murine kidneys, and from human liver tissue and murine bladder tissue demonstrating the presence of tissue-resident B cells. In humans, they are predominantly of a memory phenotype. We hypothesize that tissue-resident B cells make an important contribution to local immune responses and that their localization and function will be determined by tissue-specific environmental cues. This project aims to investigate the phenotype of these tissue resident B cells (both in mouse and human), their antigenic specificity, origin, function and interaction with other cells.

Amount: £235,304
Funder: The Wellcome Trust
Recipient: University of Cambridge

Engaging the public in health services research 15 Sep 2016

Engaging the public in health services research Engaging the public in health services research

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Does Epicardium promote Cardiomyocyte Maturation & Cardiac Regeneration? 29 Jun 2016

Human embryonic stem cells (hESC)-derived cardiomyocytes have great potential for cardiac repair and regeneration following myocardial infarction but remain significantly challenged by graft cell survival, maturation and vascularisation. The epicardium is essential for cardiac development as it forms cardiac fibroblasts, coronary smooth muscle cells, and controversially, cardiomyocytes and endothelial cells. The epicardium has emerged as a potential cardiovascular progenitor source for vascularization and cardiomyocyte support. Signalling pathways underpinning epicardial-myocardial cross-talk are postulated to be key in cardiomyocyte maturation and regeneration. Studies based on mouse models have identified several epicardium-derived paracrine factors that increase the number of cardiomyocytes and contribute to angiogenesis, although their role in cardiac maturation is unclear. This project aims to definitively characterize the role of epicardium in promoting cardiomyocyte maturation and regeneration. Key goals are: 1) To investigate the role of hESC-derived epicardial cells in the promotion of functional integration and maturation of cardiomyocytes in an in vitro tissue-engineered cardiac construct. 2) To interrogate the role of paracrine mediators including MDK and/or FSTL1 in promoting cardiomyocyte maturation and regeneration. 3) To investigate the function of hESC-derived EPDCs in promoting the survival, maturation, electrical connectivity and function of stem cell-derived cardiomyocytes in the mammalian myocardial infarct.

Amount: £270,886
Funder: The Wellcome Trust
Recipient: University of Cambridge

Control of limb movements by motor cortical circuit dynamics 08 Apr 2016

The control of limb movements has been richly investigated both at the level of behaviour and in cortical electrophysiology. However, a unified theoretical understanding of how limbs are controlled by collective neuronal dynamics is lacking. The core of this proposal is an analysis-by-synthesis approach to relate the dynamics of the motor cortex to the computational objective of limb control. In this pilot project, we will make use of recent developments in the fields of stochastic optimal control and optimization to build model cortical networks that robustly control reaching movements, in the presence of noise at all processing stages and under key physiological constraints inherent to brain circuits. We will then 1) dissect the dynamical strategies used by the model networks to achieve robust control of limb trajectories, 2) relate the model's activity to cortical electrophysiology, and 3) use the models to guide future experiments (involving optogenetic perturbations during movement planning an execution) in collaboration with Karel Svoboda's lab at Janelia Research Campus. In the long term, such models will provide unique insights into the dynamical regime of the motor cortex and suggest optimal ways of interacting with neuronal populations to restore lost function via closed-loop neuroprosthetics.

Amount: £99,500
Funder: The Wellcome Trust
Recipient: University of Cambridge

A new approach to OCD: assessing the impact of environmental stimuli on functional and dysfunctional checking behaviour. 14 Dec 2015

Obsessive-compulsive disorder (OCD) is a common and highly debilitating mental health disorder, which could be potentially treated through the disruption of maladaptive memories that contribute to the persistence of the disorder. Using an instrumental rodent model of OCD, the Observing Response Task (ORT), in which animals are trained to make unpredictably reinforced instrumental responses, but can check which response will be reinforced by pressing an ‘observing’ lever, we can dissociate functional and dysfunctional checking responses. Using this task, we have begun to investigate the influence of environmental cues on the development of maladaptive checking. We hypothesise that threatening, anxiogenic pavlovian cues in the environment promote the development of functional checking to reduce uncertainty, but that the conversion of these behaviours into dysfunctional, maladaptive responses is promoted by appetitive pavlovian cues. The proposed research aims to extend our preliminary findings, examining whether the relationship between sensitivity to aversive and appetitive pavlovian cues and the development of functional and dysfunctional checking is correlative or causal, and to determine the influence of appetitive and aversive cues on the development of compulsive checking. This would provide a springboard for future studies attempting to disrupt the reconsolidation of these maladaptive memories.

Amount: £99,959
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the link between genome reduction and pathogenicity using an emerging zoonotic pathogen. 21 Oct 2015

Bacterial pathogens very often have smaller genomes and fewer genes than their nearest non-pathogenic relatives. This pattern applies in phyla as diverse as the Firmicutes, Tenericutes and Proteobacteria. However, despite much speculation, it remains unclear why this pattern holds. I will address this question using Streptococcus suis, a bacterium that is common in non-pathogenic forms, but which also causes serious diseases in pigs and humans. My preliminary data show that S. suis has made seve ral recent and independent transitions to pathogenicity, each associated with genome reduction, and that the gene loss is non-random, suggesting that the process might be predictable. I propose to sample whole genomes of global S. suis populations. Then, I will carry out the first large-scale tests of the various hypotheses linking genome reduction and pathogenicity. This will require functional data, and new statistical approaches. Next, I will use methods from Bayesian phylogeography to place the genome reduction events in their epidemiological context, identifying factors that lead predictably to increased virulence. Finally, I will use genome reduction as a tool to uncover new virulence genes. Together, the proposed research will further our understanding of an important emerging pathogen, and of pathogenicity much more broadly.

Amount: £629,525
Funder: The Wellcome Trust
Recipient: University of Cambridge

Role of epigenetic mechanisms in random X chromosome inactivation ex vivo and in vivo. 19 Apr 2016

Developmental progression is linked to accumulation of epigenetic information mainly in the form of chemical modifications of the chromatin. One of the most striking examples of that is random X chromosome inactivation (XCI) in female mammalian embryos. This process is dependent on coating of one X chromosome by a long non-coding RNA, Xist. This in turn promotes rapid and dramatic remodelling of the chromatin. The functional relevance and exact spatio-temporal dynamics of this process remains elusive. Here I propose to address these questions by using an integrated approach. Firstly I will use an ex vivo embryo culture system to monitor the dynamics of XCI. I will further integrate that information with single cell and population based epigenomic to generate in vivo and in vitro datasets accounting to a roadmap for XCI. I aim at identifying the initial stages of epigenetic programming leading to transcriptional repression as well as genomic loci involved in nucleating these changes. I will finally address the functional relevance of X chromosome epigenetic programming by using gene knockout models and genome-wide single cell transcriptomics approach. Such work will have wide-raging implications beyond the field of XCI and can be extrapolated into other epigenetic regulatory mechanisms.

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

Consortium of Neuroimmunology of Mood Disorders and Alzheimer's Disease. 10 Apr 2014

We propose to form a consortium of academic and industrial partners to address the therapeutic challenges of Alzheimers disease and mood disorders by a shared, innovative focus on immunological mechanisms of these key neuropsychiatric disorders and their treatment by anti-inflammatory drugs. The industrial partners (Janssen and Lundbeck) will contribute drug discovery know-how and access to anti-inflammatory drugs. The academic partners will contribute expertise in neuroimaging, clinical phen otyping, animal models and informatics. The work will be organised as two programmes, focused on Alzheimer's disease and mood disorders, and four cross-cutting technical platforms (cytometry, proteomics, PET and MRI). In phase 1 (years 1-3), we will validate peripheral immunological phenotypes, e.g., cytokine levels or macrophage transcriptomes, as markers of Alzheimer's disease and mood disorders. We will seek mechanistically to link peripheral immunophenotypes to markers of central (brain) inflammation and microglial activation; to brain function and behaviour; and to longitudinal changes in the clinical phenotypes and animal models. In phase 2 (years 3-5), we will use these biomarkers in experimental medicine studies designed to test mechanism-of-action and / or therapeutic proof-of-concept of anti-inflammatory drugs in immunologically stratified cohorts of patients with Alzheimer's disease or mood disorders.

Amount: £3,434,869
Funder: The Wellcome Trust
Recipient: University of Cambridge