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Recipients:
University of Cambridge

Results

Translational Medicine and Therapeutics Programme at the University of Cambridge: 'Molecular imaging of glycosylation changes in Barrett's oesophagus to detect dysplasia: endoscopic and radiological applications.' 31 Aug 2012

To determine whether glycans can be used as molecular imaging targets. We hypothesise that labelled glycan can be detected endoscopically and thereby guide biopsies to macroscopically normal areas of dysplasia within Barrett’s oesophagus as prior to more generalized application in the aerodigestive tract.An in vivo endoscopic molecular imaging study using lectin-guided biopsies in the surveillance of BE will be completed as well as adapting a bioorthogonal chemistry approach from an animal model to label the human oesophageal glycome in human organ culture as a step towards to imaging of the human glycome without the application of lectins for imaging.

Amount: £182,345
Funder: The Wellcome Trust
Recipient: University of Cambridge

Translational Medicine and Therapeutics Programme at the University of Cambridge: 'Activating Akt mutations and metabolism: translational and therapeutic opportunities.' 21 May 2012

To elucidate the mechanisms by which the AKT2-E17K mutation affects the regulation of the downstream substrates involved in glucose and lipid metabolism in vitro approaches including western blotting, immunoprecipitation, quantitative PCR and confocal microscopy will be used. Complementary studies with AKT inhibitors will be performed and their effects on the above outcomes will be assessed. Transgenic mouse models of the Akt2-E17K and Akt1-E17K mutations have been obtained and detailed phenotyping of these mice will provide in vivo insights into the consequences of the E17K mutation as well as reveal important insights into the isoform specific functions of these enzymes. In addition, these mice will be used for pre-clinical studies investigating the clinical efficacy of compounds that impact upon AKT signalling. Collectively, the data collected from these studies will inform future clinical studies investigating the efficacy of AKT inhibitors in disease states characterised by hyperinsulinism.

Amount: £144,918
Funder: The Wellcome Trust
Recipient: University of Cambridge

Interdisciplinary Training Programme for Clinicians in Translational Medicine and Therapeutics at the University of Cambridge: Support for the 2012 MPhil Appointments. 31 Aug 2012

We propose an innovative training scheme for Translational Medicine and Therapeutics (TMAT) which builds on the exceptional conjunction on the Cambridge campus of leading scientists and clinical specialists, with an industrial research environment embraced both by international pharmaceutical and local biotech companies. Much of this is found under the same roof, the Addenbrookes Centre for Clinical Investigation (ACCI), with a track record of integrated training: academic with industrial, clinical with scientific, pharmacology & therapeutics with patient-based specialties. The novel TMAT programme will attract the brightest candidates at several levels of seniority, ranging from MB PhD students to clinical lecturers, some wishing translational skills in their chosen specialty, others not yet differentiated who may become future leaders and teachers of TMAT. Each trainee will have a customised programme. Part of this will be a bespoke, modular MSc modelled on the well-known small-group lectures and supervisions of the Cambridge final year undergraduate courses. However the centrepiece for most candidates will be a PhD including formal teaching in a wide range of translational and pharmacological skills, and a project which takes proof-of-concept studies in cell or animal systems forward to proof-of-concept studies in humans. We have assembled an outstanding faculty of PhD supervisors spanning a wide choice of skills and experience in basic and clinical science. All trainees will have the opportunity for hands-on exposure to the design and conduct of experimental medicine studies investigating the therapeutic potential of new drugs, in collaboration with our industrial partner, GlaxoSmithKline (GSK). Our product will be a new generation of clinician scientists with 360-degree vision of the complex landscape of modern therapeutic medicine, who can rise to the challenges and opportunities of 21st century drug development.

Amount: £18,531
Funder: The Wellcome Trust
Recipient: University of Cambridge

Training Programme in Translational Medicine and Therapeutics at the University of Cambridge: 'Novel therapeutics in multiple sclerosis and regulation of the immune system'. 17 Sep 2012

This project has two key goals: to investigate the role of IL7 and IL7R in the pathogenesis of multiple sclerosis and, in so doing, to educate a young physician about translational medicine. It is built upon the observations that IL7R is genetically associated with multiple sclerosis and that an antibody which antagonises IL7R ameliorated the animal model of multiple sclerosis by downregulating TH17 cells. The research question is: does antagonism of the IL7/IL7receptor pathway reduce disease activity in multiple sclerosis?The applicant will first investigate the in vitro consequences to lymphocyte biology of IL7R genotype; then explore the effect of this genotype on reconstitution of the lymphocyte repertoire therapeutic depletion. Then he will take part in a first-in-human anti-IL7R antibody trial in healthy individuals and people with multiple sclerosis. He will be involved in the design and execution of the clinical trial and the parallel laboratory studies.

Amount: £247,313
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Stem Cell Institute. 17 Apr 2012

This proposal is to facilitate creation of a world-leading centre for fundamental and translational stem cell research. The Cambridge Stem Cell Institute (SCI) will build upon previous Wellcome Trust and Medical Research Council funding by drawing together 30 research teams into a cohesive centre. These groups will ultimately be co-located in a purpose-designed 8000m2 facility to be constructed on the Cambridge Biomedical Research Campus. Platform technologies supported by a Centre grant will en able SCI to recruit and retain the most talented investigators and empower them to make ground-breaking advances in understanding stem cells and their medical applications. Fundamental research will focus at the molecular level on mechanisms of self-renewal, commitment, differentiation and reprogramming. Functional studies will address the role of stem cells in development, repair, ageing, physiology and pathologies including cancer. Disease-specific induced pluripotent stem cells will be exploi ted to unravel mechanisms of cellular pathogenesis and define drug targets. Strategies to mobilise endogenous stem cells for regeneration will be evaluated in animal models and in the clinic as will approaches based on cell transplantation. The Institute will provide comprehensive training in embryonic and adult stem cell biology and will seek, and offer unique opportunities for, bioindustry interaction and collaboration.

Amount: £4,314,068
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Stem Cell Institute Four year PhD studentships - Stem Cell Biology. 17 Apr 2012

This proposal is to facilitate creation of a world-leading centre for fundamental and translational stem cell research. The Cambridge Stem Cell Institute (SCI) will build upon previous Wellcome Trust and Medical Research Council funding by drawing together 30 research teams into a cohesive centre. These groups will ultimately be co-located in a purpose-designed 8000m2 facility to be constructed on the Cambridge Biomedical Research Campus. Platform technologies supported by a Centre grant will en able SCI to recruit and retain the most talented investigators and empower them to make ground-breaking advances in understanding stem cells and their medical applications. Fundamental research will focus at the molecular level on mechanisms of self-renewal, commitment, differentiation and reprogramming. Functional studies will address the role of stem cells in development, repair, ageing, physiology and pathologies including cancer. Disease-specific induced pluripotent stem cells will be exploi ted to unravel mechanisms of cellular pathogenesis and define drug targets. Strategies to mobilise endogenous stem cells for regeneration will be evaluated in animal models and in the clinic as will approaches based on cell transplantation. The Institute will provide comprehensive training in embryonic and adult stem cell biology and will seek, and offer unique opportunities for, bioindustry interaction and collaboration.

Amount: £1,263,038
Funder: The Wellcome Trust
Recipient: University of Cambridge

High speed super-resolution imaging with the OMX microscope. 09 Mar 2011

The imaging of fluorescent proteins in living cells has proved a powerful approach in cell biology, but many processes cannot be visualised because of the limited sensitivity and resolution of current microscopes. We seek funding for an OMX imaging system that overcomes these limitations. The OMX has a simplified light path that makes it much more sensitive than standard microscopes, and is configured to image three wavelengths simultaneously. These increase the speed of time-lapse imaging by an order of magnitude, allowing the detection of faint, fast-moving fluorescent objects that are otherwise invisible. The greater sensitivity also allows the use of lower levels of illumination, which reduces photo-toxicity and photo-bleaching for long-term time-lapse imaging of light-sensitive samples. Another major innovation is the use of structured illumination to break the diffraction limit, doubling resolution to 110nM. The OMX can perform super-resolution imaging deep inside cells at several frames/second (unlike other super-resolution microscopes), and can therefore reveal dynamic features of subcellular structure at a new scale. This microscope will be a shared resource for all cell biologists in Cambridge, and will be used to investigate topics such as mRNA trafficking, neuronal polarity, the spindle checkpoint and DNA damage foci.

Amount: £784,137
Funder: The Wellcome Trust
Recipient: University of Cambridge

High Resolution Imaging in 3D. 14 Oct 2010

The importance of microscopy in biomedical research cannot be overestimated, because it enables us to visualise the inner workings of the cell. We now know that in order for the cell to function properly, it needs to generate and maintain a number of different membrane compartments. This is achieved by packaging proteins and other molecules into vesicles that traffic from one compartment to another. The Robinson lab is investigating how different membrane proteins are packaged into the right kin ds of vesicles; the Buss lab works on the molecular motors that move the vesicles and organelles around in the cell; the Luzio lab investigates the docking and fusion of vesicles and organelles, in particular lysosomes; and the Griffiths lab focuses on how cytotoxic T lymphocytes (CTLs) orchestrate all their different types of trafficking machinery to kill target cells. Questions we will be addressing using the new microscopes include how different types of vesicles form in space and time, how t he motor protein myosin VI recruits its different partners in living cells, how organelles become tethered to each other prior to fusion, and how the immunological synapses of CTLs are formed.

Amount: £747,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

An empirical base for understanding the early phase of the epidemiological transition: Short-term and spatial variations in infectious disease mortality in England 1600-1837. 08 Jun 2011

Omran's epidemiological transition from 'pestilences and famine' through a period of 'receding pandemics' has long been assumed to have been socio-economically, technologically and medically driven. In an English context limited success has been achieved in providing an effective epidemiological explanation for a diminution in the volatility of short-term death rates associated with infectious disease outbreaks. We will investigate to what extent different locations in England shared the sam e short term experience of mortality from c.1600 to 1837, as the nation transformed from a predominantly agrarian society to an increasingly urbanised and industrial one with an integrated transport system and growing international trading and migration flows. Using existing datasets of c.550 abstractions of individual parish burial registers (a 5 per cent sample of English parishes), we will consider whether mortality peaks and troughs coincided in different locations and whether synchronisati on increased over time. We will also aim to provide a firmer and detailed chronology for the divergence in the level and stability of adult and child mortality rates that is thought to have occurred in the early eighteenth century. We will trial similar analyses on later, Civil Registration-based data and develop more detailed age profiling using existing family reconstitutions.

Amount: £95,961
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Charcot-Marie-Tooth diseases and associated defects in membrane transport. 25 Nov 2010

My overall goal is to understand the molecular mechanisms that underlie peripheral nerve myelination by Schwann cells, and the processes that become dysfunctional when disease-associated genes are mutated. I will do this by investigating Charcot-Marie-Tooth disease (CMT), the commonest inherited neuromuscular disorder. CMT4C is a severe progressive demyelinating neuropathy with apparent Schwann cell dysfunction associated with mutations in SH3TC2. My previous work investigating CMT4C has sugg ested that SH3TC2 plays a key role at the recycling endosome. I therefore plan to identify the proteins that interact with SH3TC2 in Schwann cells and to establish the effects of disease-causing mutations on these interactions. I will also develop functional assays to probe endocytic recycling and secretion in Schwann cells to determine the effect of SH3TC2 depletion, and the downregulation of other relevant proteins, on intracellular membrane transport. Furthermore, I will use Schwann cell/DR G (Dorsal Root Ganglion) neuron co-cultures to investigate the ability of SH3TC2-depleted cells to myelinate axons. Finally, as known myosin VI interacting proteins have been previously shown to influence myelination, I will establish the role of this unique actin-based motor protein in Schwann cells. By achieving a better understanding of the pathways involved in CMT, a common therapeutic target may emerge.

Amount: £796,349
Funder: The Wellcome Trust
Recipient: University of Cambridge

The biology of DEXI a novel candidate gene in autoimmune disease. 19 Jul 2011

The autoimmune diseases type 1 diabetes (T1D) and multiple sclerosis (MS) have a strong genetic basis, and recent genome-wide association studies have revealed many shared genetic risk variants, including the 16p13 region. Within this region, we have identified the DEXI gene, of unknown function and with no paralogue elsewhere in the genome as the most likely causal variant in autoimmune disease risk. The T1D and MS associated SNPs in the 16p13 region are eQTLs for DEXI expression in 2 independe nt monocyte data sets, and we have also shown their physical association with the DEXI promotor region by chromosome conformation capture. My future goal is to understand the biology of DEXI and its role in autoimmune disease pathogenesis. Key goals: 1. To evaluate changes in DEXI expression by qPCR in different stimulation conditions using cell lines, human monocytes and CD4+ cells 2. To develop a monoclonal antibody to DEXI to allow localisation of the protein within cells, quantificatio n of protein and to assist with the identification of binding partners of DEXI 3. To examine changes in immune cell gene-expression profiles by microarrray following over-expression and knockdown of the DEXI gene 4. To make recombinant DEXI and identify binding partners of this protein

Amount: £423,781
Funder: The Wellcome Trust
Recipient: University of Cambridge

Function and evolution of the atypical Notch ligands Dlk1 and Dlk2 during vertebrate development. 31 Aug 2011

Delta-like homologue 1 (Dlk1) is a vertebrate-specific atypical Notch ligand involved in development of multiple lineages in mouse. Genetic studies have shown it to be a key regulator within several pre and postnatal stem cell niches. Murine Dlk1 encodes soluble or membrane-bound protein isoforms depending on the presence of a juxtamembrane protein cleavage site, removed inalternatively spliced transcripts. Deciphering the signaling mechanisms of Dlk1 and the different functions of the Dlk1 isoforms has been very challenging in mouse. Zebrafish (Danio rerio) is an ideal model system to elucidate the fundamental aspects of Dlk1 function due to the relative ease and availability of molecular tools and techniques. In addition, Dlk1 in zebrafish is missing the juxtamembrane motif, whereas a closely related vertebrate-specific gene Dlk2, retains it, suggesting that zebrafish may use adifferent mechanism to produce membrane-bound and soluble Dlk, fulfilled by Dlk1 and Dlk2 respectively. Such proposed gene-specific functions make zebrafish a tractable model to decipher the specific roles of the secreted and

Amount: £155,658
Funder: The Wellcome Trust
Recipient: University of Cambridge

Identification of novel gd T-cell ligands cells using a forward genetic screenin haploid human cells. 12 Jul 2011

ãä T cells are a unique subset of T cells which do not require antigen processing and subsequent presentation by major histocompatibility complex (MHC) molecules, but instead recognise antigens directly. However, very little is known about the mechanisms of ãä T-cell ligand recognition. Therefore, we propose a novel gene-trap mutagenesis approach in human haploid cells to identify novel ãä T-cell ligands. There are four primary objectives that need to be met to carry out a successful screen using human ãä T cells and the near-haploid KBM7 cells: (i) establish specific ãä T-cell lines of interest; (ii) prove susceptibility of KBM7 cells to lysis by the particular ãä T-cell subset; (iii) mutagenise the KBM7 cells and

Amount: £155,810
Funder: The Wellcome Trust
Recipient: University of Cambridge

Novel strategies using 'biased' agonists at the apelin receptor for the tratment of cardiovascular disease 12 Jul 2011

Pulmonary arterial hypertension (PAH) is a fatal disease caused by genetic mutations in BMPR-II, or drugs and toxins such as monocrotaline (MCT). We hypothesize this combination of afterload reduction and positive inotropy caused by apelin, the endogenous ligand of the APJ receptor, may be beneficial to PAH. MM07, a synthetic apelin analogue and a biased agonist of APJ, is highly potent in functional assays and less likely to desensitize APJ. Preliminary results indicate that MM07 is stable in vitro and safe in vivo. Our main objective is to study the effects of apelin in animal models of PAH, and in cultured cells. Using the MCT-treated rat meodel, the ability of MM07 to prevent and reverse PAH will be tested. Then the effects of APJ agonism will be confirmed using a competitive antagonist. Additionally, MM07 will be tested in another animal model with a BMPR-II mutation. A non-peptide APJ agonist may also be used to prevent PAH. Furthermore, alteration of the apelin/APJ system will be investigated in vitro in cells from PAH patients. The consequences of these changes and connections with the BMPR-II pathway will be explored. Our findings may support the use of APJ agonists in cardiovascular diseases like PAH.

Amount: £155,834
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the effect of prenatal chronic hypoxia on the developmental programming of cardiovascular and metabolic diseases in the adult offspring. 21 Feb 2011

The aims of this PhD are to test the following inter-related questions; 1.) Does prenatal hypoxia programme insulin resistance and endothelial dysfunction in later life of the offspring, thus giving rise to metabolic and cardiovascular disease in the same individual? 2.) Does the mechanism underlying these relationships and cardiometabolic outcomes involve oxidative stress? 3.) If so, are the changes preventable by maternal treatment with allopurinol, an antioxidant, thus giving rise to a possible method of clinical intervention?

Amount: £64,692
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. 20 Sep 2011

Congenital heart disease (CHD) is one of the most common birth defects. In the left ventricular outflow tract obstruction (LVOTO) subgroup, encompassing bicuspid aortic valve, aortic stenosis, coarctation of the aorta and hypoplastic left heart syndrome or a combination, the disease burden is among the highest. Although heritability analysis have indicated substantial genetic causation, none of the published loci have been shown to explain a high proportion of cases, pointing to genetic heterogeneity. Early studies have relied on findings in individual families, defined small subsets of candidate genes and animal models. Unfortunately, they can only explain a small proportion of the observed phenotypes in humans. We will therefore exome sequence parent- offspring trios with LVOTO and examine the inherited and de novo variants identified in the light of larger CNV datasets to provide further evidence for the role of rare variants in LVOTO. We anticipate to identify known and novel causal genes, the aim is to test these variants in zebrafish. Confident variants and a previously identified causal variant in ADAMTS19 will be studied in detail in conditional knockout mice. Therefore this study holds the potential to identify novel variants and to prevent progression and complications as well as enable prevention of the disease.

Amount: £274,686
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. 20 Sep 2011

Evidence suggesting a link between iron status and type 2 diabetes (T2D) comes from meta-analyses of observational studies showing consistent associations between higher ferritin levels, the main marker of body iron status, and T2D. In addition, secondary diabetes is a common manifestation observed in patients with hemochromatosis, a hereditary disease characterised by extreme iron overload. Iron status is a modifiable factor, and hence presents a potential target for the prevention and treatment of T2D. However, important questions regarding the causal nature and sequence, as well as the mechanisms underlying the association between iron status and T2D remain unanswered. Genetic determinants of iron status may help to address some of these questions, but have not been systematically identified in adequately powered studies. This PhD will study determinants and consequences of differences in iron status using detailed phenotypic and genotypic information from large scale population studies of T2D, including almost 70,000 individuals, to assess whether and how iron status may causally affect T2D risk.

Amount: £358,433
Funder: The Wellcome Trust
Recipient: University of Cambridge