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Recipients:
University of Cambridge

Results

Role of neuronal nitric oxide in the vasodilatory response to mental stress 27 Apr 2017

Nitric oxide (NO) is a potent regulator of vascular tone. Until relatively recently, it was assumed that the isoform of NO synthase responsible for tonic NO release was endothelial nitric oxide synthase (eNOS). However, we now know that in humans, neuronal NOS (nNOS) is the primary NOS isoform responsible for regulating vascular tone in vivo. Neuronal NOS is also activated by mental stress and contributes directly to resistance vessel vasodilatation. However, our preliminary data indicate that this response is biphasic, suggesting a second mechanism underlying the vasodilatory response to stress. We hypothesise that this additional mechanism may be mediated through agonism of beta2 adrenoceptors. This hypothesis will be tested in healthy volunteers exposed to mental stress (Stroop test), using the gold-standard technique of venous occlusion plethysmography to measure forearm blood flow, coupled with intra-arterial infusions of selective inhibitors of nNOS and beta2 adrenoceptors. The key goals of this research are (i) to better define the regulation of vascular tone in healthy humans with a view to understanding potential mechanisms underlying vascular dysfunction in disease states; and (ii) gain a broader understanding of early experimental medicine approaches in the clinical setting.

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

Determining the Significance of Pathway Bias at the Calcitonin Gene-Related Peptide Receptor Family in Human Endothelial Cells 27 Apr 2017

Family B G protein coupled receptors (GPCRs), notably the calcitonin like receptor (CLR), have been implicated in cardioprotective functions. The functional GPCR is a heterodimer of CLR and one of three possible receptor activity-modifying proteins (RAMPs). There are 3 main agonists for this GPCR: calcitonin gene-related peptide (CGRP), adrenomedullin (AM), and adrenomedullin 2 (AM2). CLR is pleotropic, activating intracellular pathways through coupling to G proteins or beta-arrestins. Indeed, we recently showed, using both a heterologous yeast expression system and mammalian (HEK-293) cell lines, that the signalling bias of the CLR is dependent upon both the agonist and the RAMP. However, the cell environment of the receptor massively affects signalling bias. Therefore, to validate these results, investigation of the pharmacology of the CLR in endogenous cell lines is essential. The aim of this research is therefore to use two different human cell lines (HUVECs and HUAECs) to pharmacologically investigate CLR/RAMP2 (the adrenomedullin receptor) and CLR/RAMP1 (the CGRP receptor) when endogenously expressed. It is hoped that this will provide greater insight into the function of CLR signalling in the vascular endothelium. This information may then be used to help characterise the pathophysiology of common cardiovascular diseases such as hypertension and myocardial infarction.

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

The effect of hypoxia and and reoxygenation on inflammation in human endothelial cells 27 Apr 2017

Ischaemia-reperfusion (I-R injury is a major cause of myocardial injury during acute coronary syndrome. Initial block of a coronary artery by plaque rupture and thrombosis leads to downstream myocardial ischaemia. Reperfusion is required to prevent extensive myocardial injury, but restoration of oxygen supply can trigger further injury to the ischaemic tissue. This represents a major unmet clinical problem. Inflammation is a component of I-R injury. Ischaemia and reperfusion trigger endothelial cell activation, followed by rapid recruitment and transmigration of neutrophils and further tissue damage. This project forms part of a wider effort to develop an in vitro model of vascular inflammation during I-R injury. I will characterise the response of human umbilical vein endothelial cells (HUVECs) to hypoxia followed by reoxygenation/normoxia, in the presence and absence of tumour necrosis factor (TNF)-alpha, to mimic an additional, tissue-derived inflammatory stimulus. HUVEC activation markers, including surface expression of P-selectin, E-selectin, ICAM-1 and VCAM, will be assessed using multi-colour flow cytometry and confocal microscopy. The consequence for neutrophil adhesion and transmigration will be assessed using confocal microscopy. These experiments will demonstrate the effect of hypoxia followed by normoxia of endothelial cell inflammatory responses, and increase our understanding of the mechanisms that underlie I-R injury.

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

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

A Cluster for the Development of Dynamic 3D Nanoscopy 05 Jul 2016

Imagine if we could watch multiple molecules in living cells as they move and interact. This dream may seem years away, but it is now realistic to achieve real-time dynamic super-resolution imaging of multiple tagged proteins in three dimensions (3D) in cells and in tissues. This will allow biologists to discover large-scale patterns involving diverse structures including transport vesicles, ribosomes, and chromatin domains, all previously inaccessible because they lie in the gap between the resolution of electron (1- 2 nm) and light microscopy (200-300 nm). The "big picture" of cellular organization/information processing would emerge, with advances in understanding cell function in health and disease. While we can now do this in 2D, 3D imaging is needed to follow objects as they move out of the plane. Achieving 3D imaging is a major challenge and will require two orders of magnitude more information per cellular volume, and novel algorithms to classify, analyze, and visualize patterns from massive datasets. We propose specific innovations (Table 1) that, should allow us to achieve this over the next five years, given our team’s proven track record of success.

Amount: £660,923
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

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

Regulatory potential of repeat elements in the evolution of tissue-specific transcription 05 Jul 2016

The human genome, like all mammalian genomes, is in large part composed of decayed--but once active--repeat elements, many of which carry tissue-specific regulatory information. We hypothesise that repurposing of repeats has been critical for creating tissue-specific transcriptional regulation. Our research plan is an integrated experimental and computational strategy to systematically explore how these repeat elements have shaped the regulatory genome across the recent placental mammalian radiation.

Amount: £1,715,976
Funder: The Wellcome Trust
Recipient: University of Cambridge

A new biology of clinical outcome in immune-mediated disease 05 Apr 2016

Western medicine has developed by classifying disease into defined diagnostic categories. It is disease course after diagnosis, however, that determines a patient’s outcome, and the factors driving this variable prognosis have been largely ignored. We have focused on uncovering the biology underlying clinical outcome in immune-mediated disease. We have identified two CD8 T-cell transcription signatures that are associated with outcome but not diagnosis in four important immune-mediated diseases (Nat Med 2010, JCI 2011), and found that the signature associated with poor outcome is characterized by CD8 T cell "exhaustion" (Nature 2015). Genetic studies confirmed that pathways underlying prognosis are distinct from those underlying disease susceptibility (Cell 2013). We will explore this "biology of prognosis". Our goals are to: 1) understand the biological basis of the CD8 T-cell transcription signature that determines prognosis. This will use in vitro and human in vivo studies, alongside genetic and epigenetic analyses informing our understanding of the mechanisms of prognosis in immune-mediated disease, and allowing the refinement of biomarkers now entering the clinic. 2) develop approaches to modulate CD8 T-cell exhaustion to treat disease, by re-purposing existing drugs, defining their mechanisms of action, and testing key candidates drugs in vitro and in animal models.

Amount: £1,528,893
Funder: The Wellcome Trust
Recipient: University of Cambridge

Open Access Block Grant 2016/17 30 Sep 2016

Not available

Amount: £634,951
Funder: The Wellcome Trust
Recipient: University of Cambridge

Farming, food, and forecasting: developing outbreak resilience and sustainability in global agricultural systems. 24 Mar 2016

Crop and livestock diseases continue to pose threats to agricultural production and the provision of safe and balanced diets for healthy human populations in Sub-Saharan Africa. The problems are especially acute for invasion and spread of exotic and novel pathogen strains. Examples include rift valley fever, zoonotic diseases such as cysticerosis and echinococcus, and wheat stem rust, maize lethal necrosis and cassava brown streak disease in staple crops. The impacts and risks of epidemic spread are intensified by changing patterns in the agricultural landscapes, driven by population growth and urbanisation, and exacerbated by climate change. Conventional responses to epidemic outbreaks tend to respond reactively, inefficiently and de novo to each new threat. Building upon recent developments in the effective use of modelling to inform epidemiological policy, we have assembled a group of animal and botanical epidemiologists, together with experts in health, economics, social science and policy, to develop and test a robust framework for Sub-Saharan Africa. The epidemiological framework will address multiple scales (farm, district, national and regional) and provide planners, regulators and others with tools to minimise the risks of outbreaks, prepare for and manage outbreaks efficiently, and assess likely impacts of disease on food security, health and livelihoods.

Amount: £29,000
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

Stem Cell Biology and Medicine 30 Sep 2016

Not available

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

The stem cell/progenitor niche in the regenerating liver 30 Sep 2016

The formation of liver tissue during embryogenesis requires dynamic interactions with endo the lial and mesenchymal cells of the microenvironment, which can be recapitulated in vitro to direct the production of hepatocytes from pluripotent stem cells. The adult liver is characterised by low cellular turnover, yet it is endowed with a facultative Lgr5+ stem/progenitor population that drives tissue regeneration following damage and can be expanded in vitro as 3D liver organoids. Here, we aim to study adult non-parenchymal liver lineages – liver sinusoidal endothelial cells, hepatic stellate cells, portal myofibroblasts and Kupffer cells – as functional components of the microenvironment, or ‘niche’, in progenitor -mediated regeneration. We will characterise the spatiotemporal association of putative niche cells with Lgr5+ progenitors and differentiated progeny throughout regeneration, and perform a whole-genome transcriptomic analysis on selected niche lineages. Making use of organoid co-cultures that incorporate niche cells from regenerating livers, we will validate the ability of the niche to support Lgr5+ progenitor proliferation and differentiation. The molecular effectors of the pro-differentiation niche will be identified and the cells will be ablated in transgenic mice to confirm their niche role in vivo. These studies may elucidate novel mechanisms of liver healing and result in the establishment of organotypic liver cultures.

Amount: £43,595
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of Eros in Innate and Adaptive Immunity 25 May 2017

I will investigate the role of a novel protein, Eros, in immunity. I discovered the fundamental importance of this protein by demonstrating that Eros-deficient mice die from Salmonella infection because their phagocytes cannot make reactive oxygen species. This is because Eros is essential for expression of vital components of the phagocyte NADPH oxidase. My work represents the only paper on this protein. I have found that Eros-deficiency has effects that go far beyond the generation of reactive oxygen species. In particular: Eros regulates the expression of other key macrophage proteins including P2X7, a key activator of the NLRP3 inflammasome Eros regulates the expression of numerous cytokines from CD4+ T cells. Eros -/- T cells make 10-fold more IL-4 than control cells In mouse and human systems, I will investigate the molecular mechanisms by which Eros: controls the abundance of a subset of proteins working on the hypothesis that it is a novel component of the protein quality control pathway using structural, biochemical and cell biological techniques. controls T cell cytokine secretion. I will spend time working with John O'Shea, a world leader in this field.

Amount: £1,319,075
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of Eros in Innate and Adaptive Immunity 30 Sep 2017

I will investigate the role of a novel protein, Eros, in immunity. I discovered the fundamental importance of this protein by demonstrating that Eros-deficient mice die from Salmonella infection because their phagocytes cannot make reactive oxygen species. This is because Eros is essential for expression of vital components of the phagocyte NADPH oxidase. My work represents the only paper on this protein. I have found that Eros-deficiency has effects that go far beyond the generation of reactive oxygen species. In particular: Eros regulates the expression of other key macrophage proteins including P2X7, a key activator of the NLRP3 inflammasome Eros regulates the expression of numerous cytokines from CD4+ T cells. Eros -/- T cells make 10-fold more IL-4 than control cells In mouse and human systems, I will investigate the molecular mechanisms by which Eros: controls the abundance of a subset of proteins working on the hypothesis that it is a novel component of the protein quality control pathway using structural, biochemical and cell biological techniques. controls T cell cytokine secretion. I will spend time working with John O'Shea, a world leader in this field.

Amount: £25,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Computational tools for analysing developmental morphogenesis at the tissue-scale 05 Dec 2016

Computational tools for analysing developmental morphogenesis at the tissue-scale

Amount: £47,159
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