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Recipients:
University of Cambridge

Results

The biology of acute myeloid leukaemia 30 Sep 2016

Mutations in epigenetic regulators play a pivotal role in leukaemia initiation. We propose to study the most commonly mutated epigenetic regulator in AML: the de novo DNA methyltransferase DNMT3a (25%). It is unclear how DNMT3a mutations subvert HSC, surprisingly in bulk studies differences in methylation do not correlate with differences in gene expression, but somehow DNMT3a mutated HSC have an advantage in xenografts and survive apparently successful chemotherapy in 80% of patients. Even if a persistent clone does not predict relapse rate these patients tend to have a poorer prognosis. DNMT3a mutations are also the most prevalent in individuals with "clonal haematopoiesis". To study DNMT3a mutated preleukaemia we will use a mouse model where the most common DNMT3a mutation (R882H) and an RFP are under the control of the Mx1-cre promoter. By titrating the dose of pIpC we will generate a chimeric mouse where only ~ 20% of cells express the mutant allele. We will study clonal dynamics after challenging HSC homeostasis (through lineage tracing of the RFP) and document alterations in gene expression at the single cell level at baseline and after perturbing HSC using state-of-the-art technology (Polaris system). We will then corroborate our findings in human DNMT3aR882 preleukaemia.

Amount: £252,167
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

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

Receptor tyrosine phosphatases in physiology and disease. 21 Oct 2015

The reversible phosphorylation of tyrosine residues on proteins serves as a critical switch in the regulation of fundamental cellular processes and is controlled by the antagonistic actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Dysregulation of this balance is associated with numerous diseases as well as developmental abnormalities. Located at the cell surface, the receptor subfamily of PTPs (RPTPs) have the potential to function as key environmental sensors by me diating important processes such as cell-cell adhesion and intercellular signalling. Moreover, several RPTPs have recently been implicated in physiological functions important for human health, yet the physiological roles, substrates and regulation of many receptors remain elusive. The receptor PTPRK was identified as a candidate tumour suppressor in the mouse intestine by a forward genetics screen. In humans it is mutated in ~10% of colorectal cancers, and is a recurrent gene fusion partner, re sulting in heterozygosity. My goal is to use a multidisciplinary approach to reveal the physiological role of PTPRK, initially in gastrointestinal homeostasis, and to identify regulators and substrates that are key to its function. These advances will reveal new modes of cell signalling through tyrosine dephosphorylation and novel cellular mechanisms that serve to restrain oncogenic kinase signalling.

Amount: £1,074,941
Funder: The Wellcome Trust
Recipient: University of Cambridge

Anxiety in and about Africa 30 Apr 2016

We are applying for funding to support the travel of three speakers from the African continent. They will participate in a two-day interdisciplinary conference that examines the uses and meanings of the term ‘anxiety’ as it relates to Africa. The speakers will participate in a roundtable on the 'Vocabularies of Anxiety', which will explore how the languages with which we speak about Africa construct the continent as a site of anxiety. It will look at the importance of emotions like anxiousness in scholarly attempts to understand social, cultural, and political lives in Africa, and consider the dangers of employing a medical term as a heuristic device. Each speaker will bring a unique perspective on anxiety: personal anxieties about illness; psychiatric approaches to anxiety; and political anxieties about sexuality. By bringing together a range of research examining the various stimuli that may generate responses like anxiety we hope to invigorate an area of study that is still under-developed in the literature on Africa. Funding from the Trust will assist in bringing psychiatric and medical humanities perspectives to the fore, and ensure that African scholars are well represented.

Amount: £3,690
Funder: The Wellcome Trust
Recipient: University of Cambridge

MetaboFlow - the development of standardised workflows for processing metabolomics data to aid reproducible data sharing and big data initiatives 16 Jun 2016

The processing and analysis of mass spectrometry and nuclear magnetic resonance spectroscopy data in metabolomics is largely performed on an individual basis following local laboratory methodologies. Metabolomics lacks reproducible computational workflows based on internationally accepted standard operating procedures and this is impacting on the field in terms of reproducibility of studies and subsequent sharing of data. Furthermore, with improvements in reproducibility in analytical equipment, individual laboratories are acquiring larger, more complex datasets, which are a significant challenge to process. We propose to build, test and deliver the cloud-based Galaxy workflow, MetaboFlow, which will have computational capacity to process datasets with 1000s of samples and simultaneously capture all metadata associated with the users’ data processing workflow to allow rigorous reproducibility. We will formulate the workflow using several popular processing, feature extraction and compound identification tools and provide functionality to readily use on-line databases including our international repository, MetaboLights. The tools will be selected based on our current survey of the international metabolomics community. This proposal is a re-submission following consultation with the Trust. Specifically we have developed and implemented a plan to capture the communities’ needs, and have made significant cost savings by integrating our work with other initiatives using Galaxy.

Amount: £124,821
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating WASp-Cdc42 interaction 01 Apr 2016

Rho proteins are involved in many cellular processes. Classically, Rho proteins such as Cdc42 are involved in activating proteins that regulate the actin cytoskeleton. Deregulated Rho proteins have been implicated in tumourigenesis, invasion and metastasis of many cancers types. Cdc42 binds its effector WASp with a tight Kd, therefore peptides that mimic the ability of WASp to bind Cdc42 could be the basis for a new generation of potential anti-cancer agents. The aim of the project is to use site-directed mutagenesis to mutagenise the unstructured Cdc42 binding region of the WASp protein and quantify the binding of each mutant WASp to Cdc42. The mutant proteins will be expressed and purified in E.coli as GST-fusion proteins. Mutants will be assayed for their dissociation constant using a scintillation proximity assay. This will identify key residues that contribute to the high affinity binding of WASp and Cdc42. The wider aim of this research is to gather the data needed as a starting point for the generation of therapeutic Cdc42 binding peptides using a biased peptide library-based selection and screening experiment.

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

Hydroxylation as a mechanism for regulating the deubiquitinating enzyme OTUB1 01 Apr 2016

The hypoxic response is an evolutionary conserved mechanism that allows cells to survive low oxygen levels, by promoting activation of genes that regulate metabolism, angiogenesis, redox homeostasis and immunity. Central to this pathway are the hypoxia inducible transcription factors (HIFs) that are regulated by hydroxylase enzymes that sense intracellular oxygen levels and modify HIF activity. The role of these hydroxylase enzymes outside of the HIF pathway was unclear, but we have recently shown that the asparagine hydroxylase, factor inhibiting HIF (FIH), modifies the deubiquitinating enzyme, OTUB1, altering metabolic responses within the cell. However, how asparagine hydroxylation of OTUB1 regulates its enzymatic activity is not known. Therefore, in this project we will use an in vitro assay that we have established to determine how asparagine hydroxylation of OTUB1 regulates its deubiquitination activity and whether hydoxylation prevents binding to other ubiquitin enzymes. This vacation project offers an excellent introduction to protein biochemistry in an area of important scientific interest, and complements ongoing research within Dr Nathan’s laboratory.

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

Makerere University UVRI Centre of Excellence for Infection & Immunity Research and Training (MUII-plus) 05 May 2015

Infectious diseases remain the commonest cause of death in Africa, with HIV, malaria, tuberculosis and respiratory infections major contributors (Figure 1).1 Neglected infectious diseases cause widespread morbidity and economic loss.2 Yet effective vaccines are lacking for HIV, malaria, tuberculosis and helminths, and improved diagnostics and interventions are required. Concurrently, escalating non-communicable disease (NCD) rates3 present opportunities to explore infection-NCD relationships in ways no longer possible in resource-rich settings4 and genetic studies promise new insights into immunobiology because genetic variability in Africa is so high.5, 6 These African challenges and opportunities call for Infection & Immunity (I&I) research, in which key disciplines are immunology, molecular biology and bioinformatics. High infectious disease endemicity means that African scientists have unrivalled opportunities to conduct translational I&I research of global importance, embedded within strong epidemiological study designs (Figure 2). However, strong African capacity is necessary for sustainable, regionally-based research on African health priorities, and development in basic sciences has lagged behind clinical and epidemiological expertise.7 In Uganda, this gap hasbeen recognised: the National Development Plan8 and Vision 20409 prioritise science investment; basic science is a research priority at Makerere University;10 an African Development Bank (ADB) loan is developing laboratory infrastructure at Ugandan institutions (question(q)1j-k). The Makerere University UVRI Centre of Excellence for Infection and Immunity research and training (MUII-plusi) strategy is to drive I&I science in Uganda by bringing together scientists from the foremost health research institute (the Uganda Virus Research Institute, UVRI), and foremost university (Makerere), with their world-class, external collaborators, to support excellence in I&I research and training. Building on experience since 2008, and aligning with the Trust's DELTAS strategy [indicated in italics] MUII-plus will 1. Promote Africa-relevant I&I scientific excellence [Scientific Quality]. Transitioning from a training programme, the MUII-plus Centre of Excellence will comprise senior Ugandan I&Iscientists and young, emerging leaders, their research groups, trainees, and international collaborators: a mutually-supportive platform for world-class Africa-relevant science and training. 2. Provide career training for African I&I research leaders [Research Training] through a. Career-pathway fellowships: Uganda-based, with international collaboration and cosupervision b. Focus on bioinformatics: ring-fenced bioinformatic fellowships and project grants; shortcourses integrated with partner-network opportunities c. Focus on emerging & re-emerging infectious diseases: ring-fenced PhD opportunities at College of Veterinary Medicine, Animal Resources and Biosecurity (CoVAB) d. Improved efficiency and quality in I&I Masters training: Coordination of courses across Makerere colleges; expert input from Uganda partners, and video-conferencing from Cambridge e. Professional development and citizenship: mentored leadership experience; curriculum of workshops f. Planning for sustainability and succession 3. Utilise and enhance the UVRI-Makerere I&I research environment [Management/Environment]: a. Drive research in new laboratories developed during phase 1 (MUII-1i), in new, CoVAB, biosecurity laboratories, in the MRC-funded Uganda Medical Informatics Centre b. Strengthen research support at lead institution, UVRI 4. Engage in outreach [Citizenship]: developing communication skills; raising public awareness, networking scientists and trainees, sharing resources and research findings, interacting with policy makers, promoting implementation

Amount: £134,785
Funder: The Wellcome Trust
Recipient: University of Cambridge

Evolution of Burkholderia pseudomallei and its disease dynamics. 13 Apr 2015

Burkholderia pseudomallei is a soil organism found in many parts of the world. Through direct contact with contaminated soil/water, humans acquire infection and develop melioidosis. The disease, often fatal, displays broad clinical manifestations, with different disease patterns reported from different countries. Little is known about factors influencing the disease outcomes and its geographical signatures. We hypothesise that bacterial genetics contribute to disease outcomes, and specificity th at (i) bacterial factors impact on acquisition, disease manifestations and severity; and that (ii) the prevalence of such factors are not homogenously distributed in bacterial populations in different endemic areas. A total of 985 B. pseudomallei whole genome sequences will be employed to address these hypotheses. A phylogeny constructed from 204 global isolates will highlight geographically distinct lineages and their evolutionary timeline. Routes of infection and progression to disease will be related to genetic relatedness of 331 disease and 450 environmental isolates collected from a circumscribed area in Thailand. Clinical manifestations linked to disease isolates will allow us to identify bacterial genetic factors associated with disease specificity, as to consider their prevalence in other geographical locations. Genetic variants predicted in silico will be tested in the zebrafish embryo infection model to validate computational hypotheses.

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

Investigating the role of TL1A-DR3 in immune complex-mediated autoimmune disease. 12 Jan 2015

In this project we propose to focus on the role of the DR3-TL1A axis in autoimmune disease and more specifically on its involvement in lupus nephritis. We will determine which subset of kidney-resident mononuclear phagocytes express TL1A following immune complex-dependent FcgammaR-cross-linking. We will also investigate the relative importance of DR3 expression on myeloid cells versus lymphocytes in disease pathogenesis. Finally we will address how the myeloid cells and lymphocytes interact in the kidney in vivo and determine the role of the DR3-TL1A axis in these interactions

Amount: £80,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Tired of relapsing: manipulating T cell exhaustion as a treatment for autoimmune disease. 14 May 2014

The clinical course of autoimmune and infectious disease varies greatly even between individuals with the same condition. Greater understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T cell exhaustion inhibits the immune response, facilitating viral persistence. I have shown that a common transcriptional signature reflecting high levels of CD8 T cell exhaustion predicts poor cl earance of chronic virus (HIV) but conversely predicts better prognosis during responses to persistent self-antigen in multiple autoimmune diseases. In autoimmunity, I found that where CD8 T cell exhaustion was high a concurrent signature of CD4 T cell costimulation was low and used this signature to identify specific costimulatory signals preventing the development of T cell exhaustion during in vitro culture. As the balance of costimulatory and coinhibitory signals dictates the emergence of T cell exhaustion during chronic viral infection, I plan to test whether T cell exhaustion can be induced during in vitro and in vivo models. My ultimate goal is to exhaust an autoimmune response as a novel, targeted treatment strategy. I aim for this work to form the basis of a future translational research programme.

Amount: £1,056,174
Funder: The Wellcome Trust
Recipient: University of Cambridge

Migration, mortality and medicalization: investigating the long-run epidemiological consequences of urbanization 1600-1945. 27 Jan 2014

Today life expectancy is higher in urban than rural populations, but early modern towns and cities were demographic sinks with extraordinarily high mortality, especially among the young and migrants who were essential for city growth. The breakthrough to urban natural increase that occurred in the late eighteenth century and the eradication of the urban penalty in the 1930s mark the endpoints of major epidemiological transitions. We seek to investigate how and when cities transformed from urba n graveyards into promoters of health between 1600 and 1945. We hypothesize that the process of endemicisation and exogenous disease variation is key to the evolution of both urban and non-urban mortality regimes, especially with respect to: (i) infectious disease among the young (ii) maternal health (iii) adult migrants and their health/immunological status. This project brings together evidence from institutions (including medical and welfare), registrations of deaths and cause-of-death statistics to provide a continuous overview of the long-run pattern of urban life chances in Britain. The experiences of other European and North American populations will also be employed to elucidate the extent to which towns were drivers of epidemiological change during the first demographic transition, and the differing roles of health and welfare provision, industrialisation and migration in these processes. Recent re-emergence of an urban penalty in sub-Saharan Africa highlights the conti nuing relevance of migrant characteristics and novel or resurgent infectious diseases to patterns of morbidity and mortality in contemporary urban populations.

Amount: £1,027,006
Funder: The Wellcome Trust
Recipient: University of Cambridge

Open access publishihg costs 2014/15. 15 Sep 2014

Not available

Amount: £500,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Decoding how neutrophils self-organise their migration to sites of infection in vivo 14 Jul 2014

Neutrophils are key effectors of antibacterial immunity and inflammation. These cells often migrate in a highly co-ordinated and directed manner in order to reach sites of infection. This so-called ‘swarming’ response was shown to depend on self-production of the neutrophil attractant, LTB4. However, the cellular dynamics underlying transition from exploratory, single cell migration to collective and highly directional migration remain unclear. To address this knowledge gap I will use in vivo imaging and genetic manipulations in a zebrafish model. I will first determine the cellular triggers for LTB 4 production by neutrophils in situ. For this I will make transgenic fish expressing a reporter probe for LTB 4 production. Then I will investigate how LTB4 autocrine/paracrine signalling directs neutrophil polarity and migration. For this I will directly monitor autocrine/paracrine signalling using an additional probe for LTB 4 sensing. Finally I aim to spatiotemporally manipulate LTB 4 production and neutrophil swarming in vivo. To this end, I will develop an optogenetic tool to control the production of LTB 4 by light and use this to establish the implications of neutrophil swarming in microbial defence and tissue integrity. Thus, this study will provide a better understanding of how neutrophils self-organise their migration to sites of infection

Amount: £160,792
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role and mechanism of mycobacterial secreted virulence effectors in disease pathogenesis 14 Jul 2014

Host immune evasion, modulation, and exploitation are key strategies pathogenic mycobacteria use to establish infection and transmit to new hosts. Yet the molecular mechanisms used remain surprisingly elusive. Mutational analysis has identified several bacterial virulence determinants and their mechanisms are under active study. I plan to dissect the mechanism of action of two secreted mycobacterial virulence factors, Erp and ESAT6, which act at distinct steps of the infection process. Erp promotes bacterial growth within macrophages. ESAT6 promotes bacterial expansion in granulomas by inducing the concerted processes of apoptosis of infected macrophages and recruitment of new macrophages, which phagocytose bacteria from the dying cells. I will pursue the understanding of the molecular bases of these processes as follows: 1. ESAT6: ESAT6 has membranolytic activity that is tightly linked to its virulence. ESAT6 is necessary, but insufficient for membranolysis, suggesting additional determinants are involved. I will investigate the ESAT6-dependent mechanism of host membrane disruption by determining what is required and how membranolysis is occurring. 2. Erp: Erp induces virulence by promoting intramacrophage bacterial growth. I will determine the mechanisms whereby mycobacteria maintain membrane integrity by studying the structural and secreted roles of Erp and investigating the host defences countered by Erp function.

Amount: £160,792
Funder: The Wellcome Trust
Recipient: University of Cambridge

A genetic approach to characterising the role of the serum metabolome in type 2 diabetes 23 Jun 2014

Background: Large-scale profiling of the human metabolome could provide new insight into pathways related to the development of T2D. Mendelian randomization is an approach that uses genetic "instruments" to assess causality of observational associations, but this has not yet been adopted for systematic investigation of causality of T2D-related differences in the serum metabolome. Aims: 1. To prioritize metabolites associated with T2D for causality assessment. 2. To develop genetic "instruments" for the serum levels of high-priority metabolites. 3. To use these instruments to assess the causal nature and sequence of associations between metabolite levels and T2D. Methods: 1. High-priority metabolites will be identified through a systematic literature review of prospective studies investigating T2D-related differences in the serum metabolome, and a novel discovery in the EPIC-Norfolk T2D case-cohort study. 2. Genome-wide data from the EPIC-Norfolk and Fenland studies will be meta-analysed with publicly available data to identify genetic variants associated with each metabolite and derive and validate genetic instruments. 3. Unconfounded causal effect sizes of metabolite to T2D associations will be estimated using instruments developed in stage 2 by meta-analysing results from publicly available T2D GWAS results with new data from the InterAct T2D case-cohort study and UK Biobank.

Amount: £160,792
Funder: The Wellcome Trust
Recipient: University of Cambridge