- Total grants
- Total funders
- Total recipients
- Earliest award date
- 06 Jan 2009
- Latest award date
- 23 Dec 2009
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Acute promyelocytic leukaemia is caused by the t(15; 17) genetic translocation resulting in the PML-RAR? fusion. This disrupts the function of these two genes, interfering with myeloid differentiation. The normal function of the promyelocytic leukaemia protein (PML) is not fully understood but it appears to have a role as a tumour suppressor. Through its use in a Chinese remedy, arsenic was noted to be extremely effective in the treatment of APL. This has subsequently been validated in clinical trials. The mechanism of its action is yet to be fully elucidated; however phosphorylation of PML is detected soon after arsenic treatment, and appears to precede small ubiquitin like (SUMO) modification which ultimately results in the degradation of PML by the proteasome. This research intends to use a small interfering (si) RNA screen to knock down kinase expression and assess changes in phenotype of the response of PML to arsenic treatment, using high content imaging of HeLa cells with yellow- fluorescent protein tagged PML and a synthetic lethal approach. Validation experiments will result in a list of kinases involved in the pathway and a subsequent bioinformatic analysis will aid definition of the pathway of arsenic mediated PML degradation.
In infant humans and small mammals, brown adipose tissue (BAT) functions as a tissue for thermoregulation. This is achieved through its ability to uncouple oxidative metabolism from ATP synthesis; thus facilitating the conversion of caloric energy, especially fats, into heat. With the recent discovery that BAT is present in biologically relevant amounts in both lean and obese adults, the possibility of activating BAT as a means of increasing caloric loss in obese states are being investigated. When BAT is activated, there is a simultaneous increase in both fatty acid oxidation and synthesis. In addition, the synthesized fatty acids are extensively modified, including acyl-chain elongation and desaturation. We postulate that the ability of BAT to modify fatty acids is crucial to its function. Specifically, fatty acid chain length and saturation helps determine its intracellular fate; either towards oxidation, storage or other cellular compartments. The aim of this study is to investigate the role of fatty acid composition on BAT metabolism and asses the impact of this alteration on whole body energy balance and thermoregulation. Fatty acid elongation will be disrupted by altering the expression of Elovl6 (Elongase of very long chain fatty acid-6) in both in vitro and in vivo models. Supporting this, increasing amounts of published data supports the role of fatty acid chain length in obesity and insulin resistance. In addition, our preliminary data suggests that Elovl6 is highly expressed in BAT and its expression increases with BAT activation.
My project aims to investigate the cell-biological basis of abnormal neurogenesis and reduced brain size caused by mutations in genes associated with microcephaly including ASPM, CDK5RAP2, CENPJ, STIL, MCPH1 and PCNT. These genes all encode centrosomal proteins and they are thought to be important in the control of neural proliferation, although their precise roles in central nervous system (CNS) development and regulation of brain size are not known. To investigate this question I am working on embryonic Zebrafish retina as a model for the developing CNS due to its experimental accessibility and amenability to genetic manipulation as well as in vivo confocal time-lapse imaging. FolIowing morpholino-induced gene knockdown or expression of dominant negative constructs I will examine in detail their cell biological roles. These may include regulation of the symmetry of cell divisions and/or cell cycle dynamics. These studies will contribute to our understanding of human microcephaly and nervous system development.
Wellcome Trust PhD Programme for Clinicians at the University of Edinburgh: Structural and functional changes in the distal convoluted tubules of the kidney in mouse models of hypertension. 31 Aug 2009
I will ask: how do changes in the structure and function of the distal convoluted tubule of the kidney contribute to hypertension in mouse models? I will develop methods for defining and quantifying these changes and then use these to interrogate a hypertensive mouse model that demonstrates abnormal DCT morphology, the 11?-hydroxysteroid dehydrogenase null mouse (Hsd11b2 ?/?). My key goals are: 1) to define the ontogeny of the DCT in wild-type and Hsd11b2 ?/? mice by histological, ultra-structural and immunohistochemical characterisation 2) to create mouse reporter strains in which fluorescent proteins under the control of the promoters for the gene encoding the thiazide-sensitive transporter, Slc12a3 and Hsd11b2 are used to delineate the DCT and the mineralocorticoid-sensitive distal nephron respectively 3) to use these reporter strains to characterise changes in the DCT in response to salt-loading in wildtype, Hsd11b2 +/? and Hsd11b2 ?/? mice 4) to determine the functional consequence of cellular changes in the DCT of Hsd11b2 ?/? mice using whole-organism renal function studies and single-nephron micropuncture 5) to determine the causes of cellular changes in the DCT in Hsd11b2 ?/? mice by applying microarray expression profiling to cells isolated from reporter strains using laser capture microdissection
Wellcome Trust PhD Programme for Clinicians at the University of Edinburgh: 'Comparative genomics of the inflammatory response'. 31 Aug 2009
Sepsis accounts for over 200,000 deaths each year in the USA alone. Death from sepsis is a consequence of diffuse activation of the innate immune system. This process is controlled by transcriptional regulation within the cells of the innate immune system. A limiting factor in attempts to identify the key genes that direct this process is the limited variability within the human population. I intend to fully exploit the diversity of mammalian biology by applying comparative transcriptomics to this problem. Due to the evolutionary pressure applied to the key regulators of innate immunity, many of these regulators are likely to differ between species, and will be polymorphic within species. There is a further reason to expect that important differences exist: mice are approximately 100-fold less sensitive to LPS in vivo than humans. By comparing the transcription response to lipopolysaccharide of macrophages from mice and humans, I aim to: 1. Identify differentially-expressed LPS-responsive regulatory elements; 2. Use this knowledge to modify the LPS response of cultured macrophages; in order to, 3. Find novel therapeutic targets for modification of the innate immune response.
Wellcome Trust Clinical PhD Programme in International Health at the LSHTM: 'The roles of non-specialist health workers in mental health care provision in developing countries'. 31 Aug 2009
With the significant burden of mental illness in developing countries, the large treatment gap due principally to scarcity of skilled mental health personnel and inequities in their distribution, non-specialist health workers (professionals and non-professionals) (NSHW) are important for task-shifting within mental health care. Growing evidence for NSHWs? use in mental health care highlights the need to systematically examine their roles. India has pioneered decentralised mental health services since the 1970s but so far has had limited success in increasing coverage. Describing programmatic achievements and failures and understanding roles of NSHWs within mental health care are essential for informing policy makers and for building recommendations on effective implementation and sustainability of scaling up community mental health services in India and other low income countries (LICs). This project systematically reviews LIC mental health initiatives, which has not been done before. It explores the history and development of NSHWs? roles in mental health care provision in India through oral and written historical primary source analysis, describes NSHWs current roles through ethnographic observation and interviews and uses Delphi and workshop methods with key international and Indian stakeholders to examine the acceptability and feasibility of non-specialists? roles to inform the development of policies in LICs.
Wellcome Trust PhD Programme for Clinicians at the University of Oxford: 'Investigation of the mechanism of chromatin looping between HS-40 and the alpha globin promoter in the humanised mouse model'. 21 Jul 2009
The control of mammalian gene expression in increasingly thought to depend on long-range interaction between distal regulatory elements and promoters. The mechanisms of such physical interactions are not understood, but two hypotheses exist. The first suggests that protein/DNA complexes at cis-regulatory elements are diffusible, with resulting random collision. Specific protein interactions may then allow the formation of stabilised chromatin loops. The second model proposes that a protein/DNA complex formed at one element may ?track? along a chromosome until it encounters a protein complex at its target element, with resulting chromatin looping. This project tests these hypotheses at the alpha globin locus, using recombineering in a humanised mouse model. We will alter the position of the major regulatory element HS-40 relative to upstream and downstream inserted promoters, driving reporter genes, to define the potential polarity of the interaction between the regulatory element and its promoter. If tracking occurs equally efficiently in both directions, of two identical promoters placed at a similar distance from the regulatory element the more proximal promoter should be preferentially transcribed, distinguishing this from the diffusion model. The project has fundamental implications for our understanding of how promoters are selected in a tissueand developmental stage-specific manner and of how the timing of gene expression is regulated.
Wellcome Trust PhD Programme for Clinicians at the University of Dundee: "Innate immune signalling in response to fungal infection." 30 Mar 2009
The recognition of pathogens by the innate immune system is critical for immunity. While much attention has been focused on the innate response to bacteria and viruses, less is known about the response to fungal pathogens. This project will look at the signalling induced by fungal infection in the innate immune systems, and determine the pathways involved in regulating the production of inflammatory and anti-inflammatory mediators. An emphasis will be placed on the investigation of the role of MSKs in regulating anti-inflammatory pathways, and the possibility that these kinases may be critical in limiting inflammation following fungal infection.
In this ambitious proposal we have assembled a group of world-leading clinical and basic science researchers possessing complementary expertise to identify and tackle the causes of Parkinson's Disease (PD). The overall goal will be a fuller understanding of the molecular pathogenesis of PD as well as improved clinical assessment of the disease prodrome. The main goals of the project are: 1. To undertake comprehensive genetic analysis of a large number of well characterised PD patients to identify rare variants and novel genes that cause and predispose to disease. 2. To perform state of the art molecular and biochemical characterisation of existing and novel PD-causing gene products and their pathways to delineate the regulation and function of these proteins. 3. To clinically dissect the prodrome of PD using a large series of at risk patients. The consortium brings together both established PD researchers and senior researchers from other disciplines whose expertise brings new skills to this programme. This research should yield crucial new knowledge of the molecular pathways leading to neurodegeneration and shed insight into the causation of PD.
Asymmetry is a fundamental, yet poorly understood, feature of the CNS, critical for efficient cognitive function and disrupted in various neuropathologies. We have established the larval zebrafish as a powerful model for studying many aspects of CNS asymmetry. Our goals for this programme of research are to resolve the mechanisms by which symmetry is broken, to determine how concordance between neuroanatomical asymmetries is achieved, to elucidate the circuitry into which asymmetric neurons a re incorporated and to link activity in asymmetric circuits to behaviour. Fgf signalling is required for the leftward migration of the parapineal and we will determine how activation of this pathway is localised to leading cells of the migrating primordium. We will also address whether and how, this activation is dependent upon localised Nodal signalling. Subsequent to migration, the parapineal imposes asymmetry upon the left habenula and we will clone novel mutations in which this comm unication is disrupted and will resolve the role of Wnt signalling in this process. We will use powerful transgenesis techniques to resolve the circuitry of the epithalamic nuclei and will refine assays for behaviours that are influenced by neuroanatomical lateralisation. Finally we will directly link circuit activity to behaviour in free-swimming fry.
Engineering Solutions for an Ageing Population with Musculoskeletal & Cardiovascular Disease. 50 more years after 50. 23 Mar 2009
The ageing population is increasing in number and life expectancy. The population expects fifty more years after fifty with high levels of activity and quality of life. However, the musculoskeletal and cardiovascular systems age and degenerate, adversely affecting mobility, ability to work and quality of life. Advances in engineering and bioscience have created opportunities for novel devices and regenerative therapies, which utilise innovative biomaterials or biological scaffolds to guide the patient's own stem cells to repair degenerative tissues. Advances in patient imaging and diagnostics are enabling earlier disease diagnosis with opportunities to intervene earlier in the degenerative process and preserve healthy tissue, and potential to provide patient specific continuum of care. WELMEC will deliver: - Longer lasting joint replacements in the hip, knee and spine. - Novel regenerative biological scaffolds for degenerative joint tissues, dental reconstructions and cardiovascular surgery. - Advances in cell therapies using the patient's stem cells. - Advanced medical imaging to facilitate earlier diagnosis and intervention. - Novel protein biosensors for disease diagnosis and improved patient targeting. WELMEC will integrate over 200 engineering, physical science, life science and medical researchers with clinicians and industrialists to develop and deliver innovative therapies and patient services for the ageing population.
The genetic basis of primary biliary cirrhosis. 01 Apr 2009
Primary biliary cirrhosis (PBC) is a chronic, cholestatic liver disease which, in many cases, leads to cirrhosis and liver failure. PBC mainly affects middle-aged and older women; the prevalence in women >40 years is approximately 950 per million. There is no effective pharmacotherapy that retards disease progression. Liver transplant for PBC-related liver failure is the only effective treatment but disease may recur in the graft. There is strong evidence that PBC is a complex disease. The only consistent finding from genetic studies is weak association between PBC and HLA-DR8. A DNA collection adequate for a genome-wide association study (GWAS) has been established via the formation of a UK PBC Consortium consisting of 52 centres and all 7 UK Liver Transplant Units. This DNA collection will be used to undertake a GWAS in collaboration with the WTCCC.