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Award Year:
2008
Currency:
GBP
Recipients:
University of Cambridge

Results

Functional genomics of an imprinted domain: an integrated model for the epigenetic control of genome function. 10 Nov 2008

Aims of the programme: Genomic imprinting is process causing genes to be expressed according to their parental origin. At mammalian imprinted domains the two parental chromosome homologues function differently despite having the same sequence due to distinct epigenetic modifications on DNA and chromatin, and non-coding transcription that influences parental allele-specific gene expression. Comparing maternally and paternally inherited chromosomes results in genomic imprinting being an excellent paradigm to study cis-regulation and the epigenetic control of transcription in mammalian cells. Here we propose a programme that aims to make links between the underlying DNA sequence, conserved genomic features, epigenetic control, and gene activity and repression at an imprinted domain. Integrated in vivo experiments have been developed, focusing on the 1Mb Dlk1-Dio3 imprinted domain, to address the following key questions: What is the regional influence of large repetitive tracts in ma mmals? (experiment 1) What is the functional importance of physical juxtaposition of long-range cis-acting regulatory interactions? (experiments 2 & 3) Do evolutionary conserved non-coding regions contribute to domain-wide regulation? (experiments 2 & 3) Are large and small non-coding RNA transcripts in the domain, a cause or a consequence of genomic imprinting - what is their role? (experiments 3 & 4)

Amount: £676,577
Funder: The Wellcome Trust
Recipient: University of Cambridge

Multiple sclerosis genome-wide association study (MSGWAS). 12 Jan 2008

This application is submitted on behalf of the International Multiple Sclerosis Genetics Consortium (IMSGC) and the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) collaborative group. Together, these consortia include 18 research groups with synergistic expertise, who between them have access to a critical mass in terms of DNA samples from phenotyped individuals with multiple sclerosis. Given that GWAS genotyping is significantly more cost effective than selected marker genotyping we feel that performing a GWAS in all available cases is scientifically and financially more appropriate that using a staged approach with a modest initial screen followed by attempted replication in unscreened samples. We therefore propose to perform an extensive GWAS in 10,000 cases and compare these with data from existing population-specific control cohorts, including those provided by WTCCC. This extensive screen will provide sufficient power to identify essentially all variants with an Odds Ratio (OR) of > 1.3; 74% of those with an OR of 1.2; and even 24% of those with an OR of just 1.15. Ultimately we will combine these new data with other GWAS being performed in multiple sclerosis including the smaller GWAS we have already published.

Amount: £194,968
Funder: The Wellcome Trust
Recipient: University of Cambridge

Molecular and cellular mechanisms of cell sorting at compartmental boundaries. 10 Jul 2008

The molecular and cellular mechanisms underlying cell sorting during compartment formation are still not well understood. We propose to investigate this question in the early Drosophila embryo. This model has the advantage that cell sorting at compartment boundaries can be analysed in real time and with single-cell resolution. The key goals for this proposal are: 1) To develop methods to image and analyse cell behaviours as well as cytoskeleton activity in the vicinity of anterior/posterior ( A/P) boundaries in embryos. 2) We have found that Myosin II forms a cable at the A/P boundary, and thus we will investigate the function of Myosin II in cell sorting. In particular, we will use a conditional protein inactivation technique (CALI) to specifically inhibit Myosin II in this boundary cable. 3) We will conduct a deletion screen to identify novel genes required for cell sorting, and will investigate the relationship between these genes and Myosin II cabling. Our main goal for is to identify molecules, Myosin II, adhesion molecules or others, which are required for cell sorting at A/P embryonic boundaries in Drosophila. This will bring advances to boundary formation, but also further our knowledge of how the cytoskeleton controls cell behaviours in vivo.

Amount: £196,841
Funder: The Wellcome Trust
Recipient: University of Cambridge

HSP70 as immune potentiator for vaccines in infection and conditions of immune imbalance. 01 Jul 2008

HSP are immuno-potentiators but also can display immuno-modulatory properties. Microbial HSP70 triggers the innate immune system and elicits antimicrobial immunity as a carrier when complexed with heterologous peptides. On the other hand, HSP70 can stimulate regulatory T-cell responses producing disease-suppressive immuno-modulatory effects in inflammatory diseases. We will analyse molecular and cellular mechanisms responsible for the anti-microbial and immune-modulatory activity of HSP70 by analyzing the immune response initiating events at the level of HSP70 and innate receptor CCR5 interactions. We have shown that mycobacterial (and not mammalian) HSP70 induces signalling through human but not mouse CCR5. To further analyse the role of CCR5 we will identify regions within mycobacterial HSP70 responsible for binding human CCR5 and make the appropriate mutations so as to 'mycobacterialise' human HSP70 and 'humanize' mycobacterial HSP70. This will allow us to use human CCR5 Tg mice to analyse CCR5 in the interactions with these HSP70 molecules complexed with defined T cell epitopes. We will analyse the quality and functionality of the resulting cellular immune responses in mouse infection models (listeria and influenza). In addition we will study the immunoregulatory responses triggered by HSP70 in absence of CCR5 interaction in a natural allergic disease condition: canine atopic dermatitis.

Amount: £177,951
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanisms underlying Glucose-dependent Insulinotropic Polypeptide (GIP) secretion and function. 09 Apr 2008

Modulating glucose-dependent insulinotropic polypeptide (GIP) secretion is a potential strategy for the treatment of diabetes and obesity. However, the cellular mechanisms underlying GIP release from K-cells are poorly characterised because the cells have not, historically, been readily distinguishable from their epithelial neighbours. I recently created transgenic mouse strains expressing a fluorescent marker under the control of the GIP promoter (GIP-Venus mice), enabling, for the first time, the identification and purification of living primary K-cells. These will be characterised by electrophysiology, single cell fluorescence imaging, gene expression analysis and secretion studies, to identify agents and pathways that modulate GIP secretion and that could be targeted to control GIP release in vivo. GIP-Venus mice will be crossed with the Immortomouse to develop K-cell specific lines, which are not currently available but would be a valuable tool for research requiring a higher cell number or longer culture times. Further transgenic mouse strains will be created, expressing the diphtheria toxin receptor under the control of the GIP promoter, enabling conditional K-cell ablation in murine models of obesity. The metabolic consequences of acute and chronic GIP depletion will be investigated in these mice, to evaluate the potential effects of reducing GIP secretion in vivo.

Amount: £1,177,494
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulation and transduction of cell polarity. 20 Feb 2008

Cell polarity is critical for many functions of animal cells and loss of cell polarity is a contributing factor in cancer. We are exploiting the one-celled C. elegans embryo to investigate conserved mechanisms of cell polarity establishment and transduction. It allows study of the polarity cue and its reception by the actomyosin cytoskeleton, of the polarisation events that occur in response to the polarity cue, and of how polarisation leads to downstream events such as asymmetric spindle posi tioning. I propose both focused projects that have come out of our current studies and new screens to identify missing molecules in the cell polarity network. We will (1) carry out directed screens to identify the initial polarity cue, (2) study newly identified regulators of non-muscle myosin, and (3) investigate roles for phosphoinositides in asymmetric spindle positioning. With a long-term goal of finding the complete set of genes functioning in these processes and their relationships, we w ill (4) apply high-throughput genetic interaction RNAi screening genome-wide together with (5) biochemical purifications to further expand the cell polarity network. (6) We will carry out functional studies of newly identified genes, taking advantage of C.elegans genetics, genomics and cell biology.

Amount: £2,842,255
Funder: The Wellcome Trust
Recipient: University of Cambridge

The biological interactions of the Drosophila orthologue of LRRK-2 in the pathogenesis of Parkinson's disease. 04 Dec 2008

Parkinson s disease (PD) is a common progressive neurodegenerative disease with extra-pyramidal symptoms and cognitive decline, due to the progressive loss of dopaminergic neurons in the substantia nigra whose pathogenesis is largely unknown. Current drug treatments relieve symptoms but do not prevent neuronal cell loss. Analysis of single gene mutations that cause inherited forms of PD has advanced our understanding of the pathogenesis of PD. Mutations in the leucine-rich repeat kinase 2 (LRRK2 ) gene account for a large proportion of dominantly inherited and sporadic disease. The biological function(s) of LRRK2 are unknown and it is unclear whether LRRK2-related PD is caused by a gain or loss of function mechanism. Key goals of the proposed project are: 1. To understand the normal biology of wild type LRRK2 and its Drosophila orthologue dLrrk in relation to the pathogenesis of LRRK2-related PD. 2. To identify novel physical and genetic interactors of wild type LRRK2, and genetic in teractors of dLrrk that modulate the loss-of-function of dLrrk in a Drosophila model, in order to understand the pathways in which these proteins participate. These approaches will reveal the in vivo role of dLrrk and LRRK2, and identify potential novel therapeutic targets to prevent neurodegeneration in PD.

Amount: £622,133
Funder: The Wellcome Trust
Recipient: University of Cambridge

Biology Zone, Cambridge Science Festival, Discussion Events, Schools' Visits and Outline. 15 Dec 2008

We plan new participative Biology Zone activities at the Cambridge Science Festival in March 2009, as well as research into the impact of biomedical public engagement in science festival settings. Through school visits, a large open hands-on activity day and online 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 dimensions of advances in biomedical science. These will include genetic research, stem cell research, the effects of pharmaceutical drugs on the body, nutrition, cancer research, psychology and neuroscience, epidemiology, biostatistics, pathology, biochemistry, and physiology. Together with the Institute of Public Health, we will offer a guided walk: '8 centuries of death and disease in Cambridge'. Schools visits are planned to focus on schools which receive less science outreach, with scientists visiting schools and school groups visiting the University and research partners. We will offer at least four evening public discussions on biomedical issues. These will include a café scientifique on the ethics of brain imaging, a panel discussion on Alzheimer's research, a presentation on Darwin as a global phenomenon, and an insight into research into consciousness. We plan to run workshops bridging alternative health and scientific pharmacology. Dr Jenny Koenig plans workshops for complementary health practitioners, members of the public and school pupils on two topics: 'herbal weight-loss treatments' and 'medicines for pain and inflammation'

Amount: £26,038
Funder: The Wellcome Trust
Recipient: University of Cambridge

Bodies of Evidence: An exhibition exploring the technologies that make bodies visible. 02 Jul 2008

This application seeks support for a vital and fully integrated biomedical component for a major temporary exhibition exploring the human body at the University of Cambridge Museum of Archaeology & Anthropology (Feb 2009 - Nov 2010). The activity is part of a Leverhulme-funded interdisciplinary project based at the University of Cambridge, 'Changing Beliefs of the Human Body', that involves research groups in archaeology, classics, history, social anthropology and the Museum. The exhibition draws further insights from the history of science, biomedical research and artistic practice. The AIM OF THE PROJECT is to challenge common assumptions about the human body and to stimulate diverse audiences to explore ways that bodies are constructed, known, and contested in different time periods, across cultures, and through different disciplinary perspectives. The exhibition and associated activities will provide a forum for reflection and debate around pressing social, cultural and ethical issues to do with the human body, including well-being, race, gender, disability, and disease. Support from Wellcome will highlight and extend the biomedical components of the project and enhance public engagement with the themes of the exhibition. Three multi-sensory exhibits will stimulate interest in biomedical research and challenge visitors to learn about their own bodies. Loans from two National Museums will supplement the rich and diverse collections within the University. The provision of educational resources, a series of workshops and activities for families and community groups, and a catalogue will reach new audiences and encourage new ways of thinking about the human body.

Amount: £28,486
Funder: The Wellcome Trust
Recipient: University of Cambridge

The relationship between lineage and connectivity in the mouse cerebral cortex. 29 Aug 2008

The mechanisms by which cortical circuits are assembled remain largely unclear. Recent evidence has suggested that the excitatory neurons of the cortex preferentially form synapses with clonally related cells, hinting at a potential mechanism for circuitry formation. The goal of my project is to answer the following questions: 1. Do clones of cortical neurons form ordered synaptic connections in vitro? 2. Do clones of cortical neurons respect areal or columnar boundaries in vivo? 3. Do clonally-related cortical neurons preferentially form connections with sibling neurons in vivo? 4. Time permitting, test candidate cellular and molecular mechanisms that underlie this phenomenon.

Amount: £148,787
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of plasmalogen phospholipids in obesity and insulin resistance. 29 Aug 2008

General aims: To investigate the pathogenic role of plasmalogen depletion in the development o he Metabolic Syndrome. Soecific aims: 1) To elucidate the effect of plasmalogen depletion on energy balance, lipid and carbohydrate metabolism. 2) To characterise the metabolic effects of tissue specific plasmalogen depletion in key metabolic organs such as adipose tissue. 3) To determine the therapeutic value of replenishing plasmalogens in models of obesity and insulin resistance. ' 4) To identify the metabolic pathways altered in the context of plasmalogen depletion using a systems biology approach.

Amount: £148,787
Funder: The Wellcome Trust
Recipient: University of Cambridge

MARCH-VII, a regulator of transcriptional activity and immune cell activation? 28 Mar 2008

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: £15,912
Funder: The Wellcome Trust
Recipient: University of Cambridge

PhD Training Programme for Clinicians at the University of Cambridge. 15 Jul 2008

There is a high incidence of mosaic aneuploidy in human pre-implantation embryos, however the chance of an affected fetus is very low. We wish to explore the hypothesis that in an embryo which is a mosaic of normal and aneuploid cells, the clone of aneuploid cells might be more likely to contribute to the trophectoderm, an extra-embryonic lineage which gives rise to placenta rather than the embryo itself. First we aim to generate chimeric embryos in which normal and abnormal cells are in contact and follow the fate of both types of cells and their contribution to specific lineages; pluripotent epiblast that give rise to the embryo versus trophectoderm that give rise to placenta by time-lapse microscopy. Second, we will generate normal and aneuploid cells within a single embryo by interfering with the spindle assembly checkpoint proteins, the natural safeguard against aneuploidy and examine the fate of both cell types and mechanisms by which they reach their specific positions within the embryo and thus fate. Finally, we aim to develop and use an in-vivo chromosome marker that will allow us to directly monitor the generation of aneuploid cells in the above experiments.

Amount: £224,169
Funder: The Wellcome Trust
Recipient: University of Cambridge

The physiology and pathophysiology of unfolded protein responses. 03 Jun 2008

This project s overarching goal is to understand the molecular mechanisms involved in signaling unfolded protein stress from organelles in hope of identifying unique features that may enable manipulation of these signaling pathways to useful ends. In the better-understood endoplasmic reticulum (ER) unfolded protein response (UPRer) studies will focus on three potentially malleable aspects: A detailed molecular understanding of regulated phosphorylation and dephosphorylation of translation initia tion factor 2 will be sought, alongside a search for chemical probes to manipulate these activities in cells. These probes and genetic tools will be applied to test the hypothesis that tuning the level of phosphorylated eIF2 can promote secretion of mutant proteins and alter susceptibility of cells to ER stress. Genetic manipulation of the ER oxidase ERO1 will be applied to test the hypothesis that a hyperoxidizing ER contributes to dysfunction of mammalian cells experiencing severe ER stress an d the molecular basis of the regulation of intermediary metabolism by ER stress will be studied in effort to understand the physiological links to diseases of aging. Studies on the mitochondrial UPR will follow clues that matrix proteolysis contributes to stress signal generation and unbiased genetic screens will identify components of this signal transduction cascade.

Amount: £5,549,727
Funder: The Wellcome Trust
Recipient: University of Cambridge

Student Elective Prize for Mr Thomas Edward Parks 29 Aug 2008

Rates of Misdiagnosis of Acute Rheumatic Fever at Regional Health Centres in FIJI

Amount: £1,600
Funder: The Wellcome Trust
Recipient: University of Cambridge

Student Elective Prize for Mr Joel Wann Ee Chin 29 Aug 2008

Development of a trial audit for a pilot study on the use of Isoniazid Preventive Therapy in Zambia.

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

Does cranial cruciate ligament rupture induce plastic changes in proprioceptive neurons? 17 Jun 2008

The key goal of this project is to determine whether there is a response in the nervous system to section of the cranial cruciate ligament (CCL). Secondary goals are to: i) determine the location of responsive cells and identify them as neurons or glia; ii) determine whether the distribution and phenotype of responding cells is altered by varying the degree of inflammation within the joint; and, iii) determine whether there is a changed expression of neurotrophins within the synovial membrane after CCL section. This project, using immunohistochemistry to define the outcome measures, is designed to be a preliminary investigation into the effects of CCL section that can then be pursued in future applications through a range of other methods. Experimental animals will have the CCL sectioned and the expression of various plasticity-associated molecules will be compared between operated and non-operated sides of lesioned and sham-operated animals. In some animals the severity of inflammation within the joint will be manipulated through injection of a pro-inflammatory mediator (PGE2) or systemic delivery of anti-inflammatory drugs. Results will be analysed using ANOVA and post hoc testing

Amount: £53,143
Funder: The Wellcome Trust
Recipient: University of Cambridge

Schistosomiasis, hookworm and atopy in Uganda: IgE function, regulation and immunity. 07 Feb 2008

Key goals: Two schistosomiasis/hookworm treatment-reinfection studies in cohorts exposed to both infections, with detailed GIS and exposure analysis to give precise immunity estimates, and associations between infections controlled for overlapping transmission clustering. Study 1: compare first and second treatments for post-treatment immunological changes, and responses to in vivo Ag released from killed worms, for evidence of specific and non-specific cross regulation, affecting reinfection immunity. Specifically, measure: Schistosome, hookworm and aeroallergen IgE responses; Specific IgE function in passive histamine-release with Ag stimulation; Number/phenotype of circulating basophils and eosinophils, and tissue mast cell activity. Study 2: repeat most informative Study 1 assays, in relation to cellular responses: Whole-blood cytokine responses to schistosome and hookworm Ags; Active histamine-release from whole-blood samples stimulated native & recombinant schistosome, hookworm, aeroallergens; IL-10 and TGF-beta effects on in vitro cytokines induced by schistosome and hookworm; Skin-prick reactivity to aeroallergens; Identify cellular sources of IgE/IgE-effector modulatory molecules. Test hypothesis that: (a).Eosinophils have a regulatory role; in turn affected by immune modulators; non-responsive eosinophils are associated with reinfection susceptibility, (b).Susceptibility to schistosomiasis and hookworm is linked, via mechanisms that also affectallergy. (c).Life-stage expression and molecular structure of schistosome allergen-like Ags influence IgE and IgE-effector function triggering.

Amount: £76,244
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of the ovary-specific cap-binding protein in regulation of translation in early development . 30 Apr 2008

In early development, during the period from the meiotic maturation of oocytes to eggs through to onset of zygotic transcription in the fertilised embryo, the principal means of gene regulation is translational control of the masked maternal mRNA. The cytoplasmic polyadenylation element binding protein (CPEB) is a critical regulator of translation in early development, in organisms ranging from clam to man. CPEB binds CPE elements in the 3' untranslated regions of specific mRNAs, and controls t heir expression at the level of translational repression in oocytes, and by cytoplasmic polyadenylation and translational activation in eggs. In Xenopus oocytes, CPEB is present in a large RNP complex with several highly conserved RNA-binding partners, including Xp54 RNA helicase, Pat1, and RAP55, and inhibits cap-dependent protein synthesis using a novel pairing of the eIF4E-binding protein 4E-T(ransporter) and eIF4E1b, a close homologue of the canonical cap-binding protein. Our aims are to: I. Investigate eIF4E1b interactions with the m7GpppG cap II. Investigate eIF4E1b interactions with 4E-T and eIF4G III Identify mRNAs regulated by eIF4E1b IV. Assess the function of eIF4E1b in translational control V. Investigate how the interaction between eIF4E1b and 4E-T change during meiotic maturation when translation is activated

Amount: £277,749
Funder: The Wellcome Trust
Recipient: University of Cambridge