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Recipients:
University of Cambridge

Results

MARCH-VII, a regulator of transcriptional activity and immune cell activation? 22 May 2006

MARCH-VII, a regulator of transcriptional activity and immune cell activation? The aims of my project are: (i) To determine the role of MARCH7 in the ubiquitylation and transcriptional activity of NFAT. (ii) To determine the role of MARCH7 in T-cell activation and immune regulation in vivo.

Amount: £141,232
Funder: The Wellcome Trust
Recipient: University of Cambridge

In vivo dynamics of BRCA2 and Rad51. 26 Apr 2006

WT Studentship 4-year PhD Project Grant Project title: In vivo dynamics of BRCA2 and Rad51 A combination of biochemical, structural, cell biological and biophysical data have suggested a model whereby BRCA2 is able to sequester Rad51 monomers, with direct binding holding them at highly conserved motifs within exon 11 (the BRC repeats: Bignell et all 1997; Wong et al., 1997). However in response to DNA damage, BRCA2 is thought to directly facilitate Rad51 targeting and oligomerisation during HR. The biophysical support for this model comes from a fluorescence recovery after photobleaching (FRAP) study of GFP tagged Rad51. Rad51 was detected in an immobile fraction in living cells due to self association and also due to the interaction with BRCA2, and it was the BRCA2 population which was found to specifically increase in mobility in response to DNA damage. Biochemical data showing that the expression of individual BRCA2 BRC repeats can block Rad51 filament formation to varying degrees in vitro is also in agreement with this model. However, it raises a further question about the significance of this observed heterogeneity in the Rad51 binding regions, which is also implicit in the observation that mutations in different BRC repeats are associated with varying risks of carcinogenesis. To study the dynamic switch in BRCA2 function from sequestration to mobilization, recent unpublished work in the Venkitaraman lab has begun to study the in vivo dynamics of the protein using FCS. FCS measures fluctuations in fluorescence intensity inside an illuminated volume in the order of one femtoliter, using a confocal microscopy setup. Through a time correlation of the signal, the hydrodynamic and photophysical properties of a fluorescently tagged species can be determined as it diffuses through the observation volume. Typically, mobility coefficients and local concentrations are calculated. Although less well established than other non invasive fluorescence-based imaging techniques such as FRAP, FCS provides more powerful insight into certain parameters.

Amount: £141,232
Funder: The Wellcome Trust
Recipient: University of Cambridge

Epigenetic Programming of the mouse germ line. 23 Jan 2006

Epigenetic Programming of the mouse germ line Major epigenetic reprogramming of the germ line occurs in the primodial germ cells (PGCs) in which parental imprints are erased. This is brought about by the dynamic removal and re-establishment of epigenetic marks in the nucleus, essentially involving histone modifications, DNA (de)methylation and chromatin remodelling. Both arginine and lysine residues can be methylated and one of the ways these histone modifications transmit their biological signals is through local binding factors (effector proteins) that recognise the distinct methylation marks. Currently, little is known about the identity of effectors that recognise methyl-arginine modifications. Very recently, tudor-domain containing proteins were shown to be able to bind to symmetric methylated arginines in polypeptides and were postulated to be general methyl-binding proteins. These are strong candidates that may be general effectors of methylarginine on histone tails. I will examine if this putative histone methyl-binding capability exists, and if so, how tudor proteins may potentially contribute to the germ line chromatin state during epigenetic reprogramming. Notably, my preliminary data have shown that several of these tudor-domain containing proteins appear to be restricted to the germ line, and absent in the soma. This strongly suggests that tudor family of proteins may have uncharacterised functions in germ line development in addition to a putative methyl-arginine binding ability. Although it remains to be established if tudor proteins are methylarginine effectors, their potential involvements in germ line development are interesting in their own rights. Finally, I am also aware of the possible wider roles of tudor proteins in pluripotency, and will address this possibility.

Amount: £23,661
Funder: The Wellcome Trust
Recipient: University of Cambridge

The structural biology of cell signalling and regulation: multiprotein systems and the achievement of high signal-to-noise ratios. 27 Apr 2006

The control of cell differentiation, growth and proliferation is mediated by the assembly and disassembly of multiprotein complexes. My group has studied the 3-D structures of many such complexes in order to understand the nature ofthe interactions, organisation and cooperativity; examples are FGFR, human recombinase Rad51, the breast cancer associated gene product BRCA2, and Cdk6 with cell cycle inhibitor p19INK4d. We have shown that pair-wise interactions are often weak and ill-defined but lead to cooperative assembly of multiprotein complexes with well defined structures, so providing better signal-to-noise ratios in signalling. In this proposal I focus on other features that are shared between multiprotein systems at the cell surface, in the cytoplasm and in the nucleus. I plan to investigate 3-D structural features of complexes where: 1. One or more components are disordered prior tobinding. 2. Higher order clustering modulates signal transduction.3. Glycosylation controls receptor interactions. 4. Different assemblies regulatedifferent signalling pathways. In order to achieve these objectives I plan notonly to extend studies on systems where we have worked before, for example FGFR, Met receptor and Xrcc4; but also to initiate work on others where we have only preliminary studies, such as the Notch receptor. The research involves protein expression, purification, characterisation of complexes, crystallisation, X-ray analysis and bioinformatics.

Amount: £1,454,930
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of Z alpha-1 antitrypsin in the pathogenesis of emphysema. 23 Feb 2006

Alpha-1 antitrypsin (AT) is a major serine proteinase inhibitor whose main function is to protect the lung from proteolysis by neutrophil elastase. The Z variant (E342K) is prone to form polymers which accumulate as inclusions in the hepatocyte predisposing Z-AT homozygotes to cirrhosis. The low plasma levels of Z-AT predispose early onset panacinar emphysema. Polymeric AT may in part be responsible for the previously described exaggerated inflammatory response in Z-AT homozygotes. Polymers of Z-AT are present emphysematous lungs, and are chemotactic to neutrophils and preliminary data suggests that they also induce the secretion of interleukin-8 from type II alveolar cells. The factors that cause the formation of polymers within the lung are not known. In vitro, their formation is accelerated by increasing concentration and temperature. Furthermore, Based on the structural biology of polymerisation we have identified peptide inhibitors of polymerisation. The key scientific objectiv es of this work are to (1). elucidate the factors that cause polymerisation of Z-AT within the lung (2). assess whether polymeric AT causes Interleukin-8 secretion from type II pneumocytes (3). to assess whether potential therapeutic agents are efficacious in vivo.

Amount: £126,420
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Institute for Medical Research (CIMR). 20 Sep 2006

A major objective for CIMR over the next 5 years is to better understand protein localisation, function and metabolism in a range of diseases in which genetic studies have identified the causative genes. Underpinning our core facilities is essential to achieve this objective and will provide added value to the considerable investment that the Wellcome Trust is already making to our scientific activities. Our present scientific goals are: (i) determination of the molecular mechanisms of intracellular protein aggregate formation and breakdown in health and disease, including the identification of novel therapeutic targets for protein conformational diseases; (ii) identifying and characterising the molecular machinery of intracellular membrane traffic and determining how traffic pathways are coordinated, regulated and modified in health and disease; (iii) the identification of genes, proteins and pathways increasing susceptibility to, or protection from, autoimmune diseases; (iv) determining the transcriptional regulation of haematopoietic stem cells. Our proposal includes funding of core specialist scientific staff, annual research retreats, funds to encourage young clinicians back into research and a case for 2 PhD students per annum. We aim to make CIMR a flagship in the UK for interdisciplinary research at the interface between clinical and basic research.

Amount: £4,084,076
Funder: The Wellcome Trust
Recipient: University of Cambridge

Centre of excellence in diet and physical activity public health. 16 Sep 2008

The proposed Centre of Excellence at the Institute of Public Health, Cambridge focuses on two main themes of the UKCRC initiative by promoting research excellence in public health research related to diet and physical activity. These two behaviours are strongly linked to the rise in non-communicable diseases such as cancer, lschaemic heart disease stroke and type 2 diabetes which are major contemporary public health problems. Rather than tackle these behaviours separately, the proposed Centre explicitly considers them together. The problem of the rising prevalence of obesity demonstrates the need for this approach as any public health solution solely focused on either diet or activity is unlike be successful. The Centre brings together researchers with an established international track record in diet and physical activity research, epidemiology, biostatistics, health economics, behavioural science, intervention development and evaluation. The Centre builds on the strong foundations of expertise in the measurement and descriptive epidemiology physical activity and dietary behaviour, the study of the links between diet and activity and chronic disease and the development of preventive interventions. As a Centre within an existing institute with multiple MRC Unit contributions, there are clear established links to under-pinning methodological research for public health science. The overall goal of the Centre is to develop effective public health interventions for changing population-level diet and physical activity behaviour. The Centre's work is organised around 4 age-defined research programmes aimed at pre-school children; school aged children and adolescents, working age adults and retirement age adults. Within each programme a range research projects is planned, which make use of a core organisation and research infrastructure. The projects range from early work on understanding the determinants of activity and dietary behaviour, through intervention development to evaluation of effectiveness.

Amount: £1,559,515
Funder: The Wellcome Trust
Recipient: University of Cambridge

Genes and Mechanisms in Type 1 Diabetes. 07 Jun 2007

Type 1 diabetes (T1D) has a strong genetic basis, and results from autoimmune destruction of the pancreas. Several genes are known to be important, but many others have not yet been identified. Preliminary results from a genome scan by the Wellcome Trust Case Control Consortium have revealed a region on chromosome 16p13 associated with T1D susceptibility. This area contains 3 potential candidate genes: KIAA0350, MHC2TA and SOCS1, which are all known to influence immune responses. MHC2TA has pre viously been ruled out as a casual variant, however the role of the other two genes in T1D has not been established. The key goals of the proposed project are to investigate SOCS1 and KIAA0350 genes to establish: 1. Whether gene polymorphism is associated with risk of T1D 2. Whether phenotypic differences are present in individuals with susceptible and non-susceptible genotypes, potentially implying a mechanism by which pancreatic destruction might be promoted. As well as improving out improve our ability to predict which individuals are at a genetically higher risk of T1D, evaluation of the function of genes leading to an increased risk of T1D, will provide insights into gene function and pathogenesis of disease, allowing novel therapeutic strategies to be developed.

Amount: £294,835
Funder: The Wellcome Trust
Recipient: University of Cambridge

Open Access award. 31 Oct 2006

Not available

Amount: £30,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Biology Zone: Cambridge Science Festival, Schools' Visits and Online 30 Jan 2007

We intend to run novel participative Biology Zone activities at the Cambridge Science Festival during National Science Week in March 2007, through school visits and online through interactive content, audio and video material. The Biology Zone will engage school pupils, young people and adults with interactive presentations, demonstrations, and take-home activities on the health, social and ethical dimension of advances in genetic research, stem cell research, the effects of pharmaceutical drugs on the body, nutrition and farming, cancer research, psychology and neuroscience and infectious disease. In collaboration with partners with extensive track records in this area, the Biology Zone will involve scientists presenting interactive experiments, displays and computer presentations, and discussing issues with 3,000 visitors of all ages. Schools visits are planned to reach a further 1300 pupils, focusing on schools in challenging circumstances, with a combination of scientists and artists visiting schools and school groups visiting farms and other sites of interest to support learning in biological subjects. Online activities will bring interactive biomedical brainteasers and puzzles, targeted at 11-18 year olds, on to the Cambridge Science Festival site to give learning an extended dimension. We will also make Podcasts and audio downloads of biomedical content at the Cambridge Science Festival available through our website, in partnership with the Naked Scientists' radio show. Videos of biomedical lectures and of Festival attendees presenting their views will also be made available through our website. These online activities will engage at least 10,000 visitors.

Amount: £25,500
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of envelope proteins in the outcome of lentivirus infections in hominoids 23 Mar 2007

The overall aim of the project is to better characterise the non-pathogenic HIV-1 and SIVcpz infection of chimpanzees, where a high viral load is maintained without progression to AIDS, and to determine the factors that result in this non-progressive outcome. Determining the differences between pathogenic infection of humans and non-pathogenic infection of our closest relative will provide unique insight into the pathogenesis of HIV-1 infection, which remains poorly understood after over 25 years of research. Key differences described so far are that non-pathogenic infection of chimpanzees does not result in chronic immune activation or NK cell dysfunction shown in pathogenic infections of humans. In both of these phenomena, the majority of effected cells are not infected, suggesting a viral protein can induce these effects independently of cellular infection. Viral envelope on the viral surface, or in a soluble form following shedding, can interact with a number of receptors. Interactions with NK-cells and HIV-1 envelope leads to NK-cell dysfunction, and interaction with T -cells can induce virological synapses, a structure similar to the immune synapse involved in T-cell activation. This project will focus on immune dysfunction resulting from direct interactions between HIV-1/SIVcpz envelope and cells of the immune system purified from cryopreserved human and chimpanzee PBMCs.

Amount: £144,363
Funder: The Wellcome Trust
Recipient: University of Cambridge

Infection and Immunity The origin and function of the FAP + cels in infected and uninfected wounds 23 Mar 2007

The aim of the project is to define the origin of the FAP _ cells in the tumour stroma. The first question to be asked is whether they are composed of haematopoietic cells, mesenchymal cells or a mixture of both. If they are haematopoietic in origin they could represent a case of a haematopoietic to mesenchymal transition as has been proposed for the stellate cells in the liver which are c045 but come from c045 progenitors (Miyata E et al. 2008). Transdifferentiation has also been proposed to occur from mesenchymal stem cells (MSCs) (Uccelli A et al. 2008) and it could be the case that these contribute c045 cells to the stroma. To answer this question OVAGFP BAC transgenic and non-transgenic mice would be sublethally irradiated and then would be reconstituted with sorted haematopoietic stem cells from non-transgenic or transgenic mice, respectively, differing at the thy1.1 locus. These mice would then be injected with LL2 or 816 tumour cells and the resulting tumours analysed for the presence of CD45+ and CD4s EGFP+ cells in the tumour stroma. This would allow the contribution of both non HSCs and HSCs to the FAP compartment to be ascertained. - Along with this lineage analysis further characterisation of the FAP cells would also be carried out. FACS-sorted GFP+ stromal cells could be further analysed to examine their surface markers. Recently it has been suggested that FAP _ marks human MSCs from the bone marrow (Bae S et al. 2008). This study was limited by the fact that it used commercially obtained MSCs and so it is unsure how well it applies to in vivo but it would be worth looking for GFP+ cells in the bone marrow. If these were found, they could be analysed for expression of CD45, indicating HSCs, or for several other markers as CD45.CD73.CD9<rCD105+ cells would indicate an MSC origin. Cells from the tumours would also be analysed. To do this tumours would be obtained and single cell isolates prepared this could allow the phenotypes of the CD45+ and c045 populations to be better defined by other markers. An example would be looking for alpha smooth muscle actin which would define 'reactive' myofibroblasts in the stroma on CD45- cells. Finally functional studies would be performed to see what these cells were doing. They could function as APCs despite being CD45 , as has been reported for the stellate cells in the liver (Miyata E at al. 2008; Winau F et al. 2007). It would also be worth checking if they were anti-inflammatory for example through production of heme-oxygenase 1, or whether they produce retinoic acid which has been shown to be involved in inducing regulatory T-cells (Xiao S et al. 2008). This latter possibility again ties in with the hepatic stellate cells in the liver which also store a large amount of vitamin A (Reuben A, 2002).

Amount: £144,363
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of nucleophosmin in maintaining genomic ns inintegrity and implications in lymphomagenesis. 30 Jan 2007

The role of Nucleophosmin in maintaining genomic integrity and implications in lymphomagenesis 1) To assess whether the NPM gene is mutated/deleted in lymphoma. 2) To examine the role of NPM in maintaining genomic integrity. 3) To examine the contribution of NPM haploinsufficiency to NPM-ALK-induced lymphomagenesis in a mouse model.

Amount: £10,062
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulation of cell adhesion dynamics during epithelial cell movements. 10 Jul 2007

Half way through embryonic development, the epidermis of Drosophila exhibits a gap covered by a different epithelium, the amnioserosa. Dorsal closure is the process whereby interactions between the two epithelia establish epidermal continuity. This process is an excellent model system to study the cellular processes involved in epithelial morphogenesis. While much attention has been focused on the cytoskeleton and its regulation during dorsal closure, little is known about the regulation of the cell-cell adhesion systems which must play a key role in the process ensuring the continuity of the epithelia and mediating their interactions. Here we propose to perform a quantitative cell biological analysis of the regulation and coordination of the components of the adherens junctions during dorsal closure. Using state of the art microscopic techniques we shall probe into the spatial and temporal dynamics of the interactions between DE-Cadherin and D- -catenin, Armadillo, as well as betw een a-catenin and Armadillo, and how these impinge on the coordinated movement of the epidermal sheet. In parallel we shall analyze how these molecular events that take place at the cellular length scale contribute to the behaviour of specific tissues and to the overall morphogenetic movement.

Amount: £281,392
Funder: The Wellcome Trust
Recipient: University of Cambridge

To discover further genes that determine human brain size. 28 Jun 2007

We have ascertained and phenotyped families with ten different autosomal recessive disorders in which primary microcephaly (a significantly reduced brain size at birth) is the key feature. We have sufficient affected family members to find each disease gene. We will use the well-tried and reliable method of looking for human mutations leading to reduction of brain size: genetic linkage; search for ancestral shared haplotypes; bio-informatics analysis of transcripts in the linked region; seque ncing candidate transcripts; assessment of any mutations found by bio-informatics, presence or absence in control populations and functional analysis. A disease gene will be identified by finding pathogenic mutations in the linked families. Having found each gene, we will perform, 1. Detailed human embryonic and foetal brain expression studies and pooled cDNA to determine adult tissue expression. 2. Assess cell localisation, if necessarily throughout the cell cycle and in different huma n cell types. 3. If possible, within the auspices of the project: derive a plausible hypothesis of gene/protein function; and show how mutations alter gene or protein function by whatever necessary methodology. The successful conclusion of this research will be a peer-reviewed article on each disease gene; we would aim for at least six.

Amount: £460,856
Funder: The Wellcome Trust
Recipient: University of Cambridge

Structure function relationships of rotavirus RNAs - significance for the replication cycle. 24 Apr 2007

Rotaviruses are a major cause of acute gastroenteritis in infants and young children worldwide, leading to approximately half a million deaths per annum. There is no recognised specific antiviral treatment, and whilst rotavirus vaccines are under development they have not been universally applied yet. Rotaviruses package 11 different RNA segments into each virus particle. Reassortment between viruses occurs by exchange of corresponding RNA segments. Much published work indicates that this precis ion of packaging is a consequence of specific RNA structures in the RNA segments and that the RNA fulfils a structural role in the virion. We have performed preliminary analysis of potential RNA secondary structures in the termini of rotavirus segments and have identified conserved sequences and conserved potential intra and intermolecular pairings between the segments. Our aim is to define the RNA packaging signals in rotaviruses by structural analysis using free energy parameters, biochemical probing, sequence comparison and NMR spectroscopy. We will validate solved structures functionally by interaction with rotavirus core proteins and in replication assays and attempt to develop an in vitro packaging system. This work will identify new candidate therapeutic targets and has potential in vaccine development. It will contribute towards a reverse genetics system for rotaviruses.

Amount: £397,294
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the genome packaging mechanism of influenza A virus. 27 May 2008

Influenza A virus genome consists of eight segments, all of which encode essential gene products; thus, one copy of every segment needs to be incorporated for the virus to be viable (1- 3]. Genome packaging of influenza A virus is thought to rely on interactions between the packaging signals found in the eight segments which have been proposed to be arranged in a 7+1 array within the virion. The ultimate goal of this project is to test the 7+1' array hypothesis, to identify the putative order of segments in the 7+1 conformation and to define the inter-segment interactions important for packaging of the virus genome. Specifically, there are three aims: 1) Each viral segment has packaging signals at the tenmini. Previous work suggests that certain combinations of packaging mutations in different segments affect virus fitness to a much greater degree. Thus, the first aim of the project is to identify which pairwise mutant segment combinations have a greater effect on virus viability in order to determine which interactions are the most important; this will suggest the position of the segments within the 7+1 array. 2) Previous studies have shown that packaging mutants can regain fitness by generating 'pseudorevertants', i.e. viruses which acquire compensatory mutations without reverting the original ones. This project aims to investigate the 'pseudorevertants' from double packaging mutants which would allow identification of important intersegment interactions. 3) Certain packaging double mutants are lethal. It is possible that absence of crucial intersegment interactions would result in disruption of virus budding. This project will examine the hypothesis that certain double packaging mutants have a budding deficiency.

Amount: £148,684
Funder: The Wellcome Trust
Recipient: University of Cambridge

Allergen like molecules in Schistosoma haematobium: roles in human immunity and acute disease. 27 May 2008

This project will be the first systematic study of 1111tigenic proteins from Schistosoma haematobium, a major helminth pathogen of man. lgE-mediated immune mechanisms are central to immunity to parasitic worm infections and allergy. Recombinant forms of S. haematobium Tegumental Allergen-Like (ShTAL) proteins will be used to characterise patterns of anti-ShTAL lgE responses and IgE-mediated effector functions in human cohorts living in S. haematobium endemic areas of Mali, and in travellers returned to UK with recently acquired infections. These data will be analysed in relation to human susceptibilitY and immunity to infection, the regulation of human IgE and lgE-mediated effector mechanisms, and acute and chronic schistosomiasis morbidity. Specific aims: To identify tegumental allergen-like (TAL) proteins in S. haematobium using adult worm and egg EST databases. To create expression profiles of S. haematobium TALs (ShTALs). To express and purify recombinant ShTAL proteins. To establish patterns of antibody isotype responses to these ShT ALs in human sera collections from studies in aS. haematobium high transmission area of Mali. To test the ability of individual ShTALs to trigger human lgE-dependent immune effector mechanisms. To analyse anti-ShTAL antibody isotype responses in relation to age, sex, intensity of infection and the effects of chemotherapy. To analyse antibody isotype responses to the ShTALs (and circulating cytokine levels) in relation to human immunity, reinfection and urogenital morbidity. To analyse anti-ShTAL IgE and IgG subclass antibody responses and passive and active histamine release, in travellers returned to UK with S. haematobium infection.

Amount: £148,684
Funder: The Wellcome Trust
Recipient: University of Cambridge