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Recipients:
University of Oxford

Results

Development of novel meta-machine learning algorithms for the integration of genomic and neuroimaging data for genetic pathway discovery: application to Parkinson's disease and schizophrenia. 27 Jan 2011

My proposed study is focused on computational approaches to identify genetic risk factors via the fusion of genomic and neuroimaging data on Parkinson's Disease and schizophrenia in order to discover pathways of genetic changes that are associated with increased risk for these diseases and that act directly on neuroimaging intermediate phenotypes associated with each disease. In order to do so, I will develop a novel meta-machine learning algorithm for the integration of these two disparate sources of data to increase the ability to detect pathways impacting on disease and imaging phenotypes.

Amount: £70,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Discovering the function, structure, and evolutionary impact of proteins created de novo (i.e. not by duplication), in particular in viruses and in bacteria. 07 Dec 2009

Novel proteins are thought to be created mostly through gene duplication. However, recent studies showed that de novo protein creation occurs at an unexpectedly high rate. I have shown that a particular subset of de novo proteins, those encoded by viral overlapping genes, are abundant and relatively easy to identify. These proteins have unusual sequence and structure properties (being unstructured or having previously unobserved structural folds), and specific functions (usually associated with viral pathogenicity). In collaboration with two experienced investigators with complementary skills, I will collect and curate a much larger dataset of several hundreds de novo proteins from viruses (mainly) and from bacteria. I will study their sequence, evolution, function, and structure, through bioinformatics and experimental approaches. In particular I aim to solve about ten of their 3D structures. This will provide a new, experimental approach to understand the evolution of protein stru cture and possibly challenge the belief that nature creates proteins only according to a limited number of folds. This research will also improve our scant knowledge of viral accessory proteins, which are often created de novo, and may uncover features associated with virus emergence. Each step of the project will generate findings that can be published independently.

Amount: £224,299
Funder: The Wellcome Trust
Recipient: University of Oxford

Are non-malarial fevers in pregnancy significant causes of under recognised maternal mortality and morbidity and low birth weight in Laos? 16 Jun 2010

Laos had one of the highest maternal mortality rates in Asia at 405/100,000 live births with slow progress in reducing maternal mortality rate. Although obstetric problems are clearly important, the abundance and diversity of infectious diseases in Laos suggests that these may also contribute to maternal mortality and morbidity and poor birth outcomes. That this may be so is suggested by a research project on the aetiology and impact of fever during pregnancy in Vientiane, Laos, for which Dr Vilada Chansamouth is the PI. This has suggested that dengue fever, scrub typhus and murine typhus are key causes of febrile illness during pregnancy and have adverse pregnancy outcomes. However, Vientiane, being the main urban centre in Laos, is atypical of the country and we propose to determine the incidence of fever in pregnant women in a poor rural southern province (Salavan) in a cohort study of 1,800 pregnant women and to determine the causes and impact of non-malarial fevers amongst these women and their newborns. These are the key goals.

Amount: £126,268
Funder: The Wellcome Trust
Recipient: University of Oxford

MA in History of Medicine 21 Sep 2010

Not available

Amount: £24,497
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £153,330
Funder: The Wellcome Trust
Recipient: University of Oxford

4 year PhD in Neuroscience - Assessing and modelling the effects of antidepressant medication on the learning of emotional and non-emotional information 19 May 2010

This project will use behavioural and neuroimaging techniques to test two competing models of the time lag in clinical effects of antidepressant drugs. Both these accounts predict improvements in learning with antidepressant treatment but critically expect a different balance of effects on emotional versus non-emotional learning processes. A series of studies will use behavioural and neural markers of learning and plasticity in healthy volunteers to explore the effects of drug treatments relevant to depression and anxiety. Ultimately, the aim of the project is to improve our understanding of the mechanisms of action of antidepressant medication with a view to using this knowledge to inform the early-stage development of novel treatment regimes.

Amount: £151,290
Funder: The Wellcome Trust
Recipient: University of Oxford

Genome-wide DNase 1-hypersensitive sites ins byprofile in different mouse strains by DNase-sequencing. 15 Feb 2010

1. Construct massively parallel sequencing libraries from DNAse treated DNA obtained from erythroblasts from the reference strain, C57BL6/J. A library with the correct size distribution and validated by qPCR, will be used as the basis for comparison with data from other strains and as validation with array-based methods for DNAse hypersensitivity sites detection. 2. Construction of libraries from eight strains (A/J, AKR/J, C3H/HeJ, BALBc/J, CBA/J, DBA2/J and LP/J) previously used in a genome-wide mapping experiment of multiple phenotypes (included full blood count) 3. Mapping of hypersensitivity sites onto the whole genome sequences of these strains (obtained from the Sanger institute) 4. Validation of the functional involvement of sequence variants and comparison with the position of quantitative trait loci contributing to haematopoietic phenotypes

Amount: £1,736
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigating the function of the non-specific X-linked mental retardation protein IIRAPL. 18 Jan 2010

Non-specific X-linked mental retardation (NS-XLMR) affects approximately 1 in 1 ,000 males and mutations in a series of genes have been associated with this inborn disease. By examining the normal function of these genes and how their mutations result in cognitive impairment, it is hoped that we will develop a general understanding of this condition and thereby identify new avenues for treatment. Mutations in a gene called the IL-1 receptor accessory protein-like gene (IL 1 RAPL) have recently been shown to be responsible for NS-XLMR. In this DPhil project the student aims to examine the cellular function(s) of IL 1 RAPL and how this protein contributes to NS-XLMR. To achieve this goal the work has been divided according to the following experimental aims: (1) To characterise IL 1RAPL in mammalian neurons by determining its distribution and subcellular localisation. (2) To examine how IL 1 RAPL contributes to presynaptic development and function in developing neurons. (3) To examine how IL1 RAPL contributes to postsynaptic development and signalling in developing neurons.

Amount: £13,203
Funder: The Wellcome Trust
Recipient: University of Oxford

An investigation into the e biology and function of the Themis B cell homologue Icb-1. 18 Jan 2010

An investigation into the biology and function of the Themis B cell homologue lcb-1 The generation of an effective adaptive immune response to pathogens depends upon the appropriate selection and regulation of antigen-specific lymphocytes. T and B cell development and selection are both driven at different stages by the encounter between antigen receptors (TCRs and BCRs respectively) and target antigens. Positive and negative selection is a function of developmental stage and depends on the strength of the interaction and the presence of accessory signals [1-2]. How these external signals are integrated with the internal milieu leading to death or survival is one of the great mysteries in immunology. Despite the fact that a high effort has been put into studying these processes, many factors and pathways remain unknown. There is therefore an urgent need to understand more about these processes. One of the methods to identify new pathways involved in immune regulation is to introduce mutations into mice using ethyl-nitrosourea (ENU) and then screen for animals carrying immune phenotypes [3). This approach recently lead to the identification of a new gene family including protein Them is (with two other groups) which was shown to be essential in T cell selection [4-6]. lcb-1 is a close homologue to Themis, which is expressed in B cells and cells of the myeloid lineage. lcb-1 is speculated to have similar roles in B cell development. Our laboratory has a longstanding interest in B development and has generated a variety of transgenic tools for studying the positive and negative selections of B cells at the immature stage and during affinity maturation in the germinal centre [7]. The aim of this project is to study the functions of lcb-1.

Amount: £87,120
Funder: The Wellcome Trust
Recipient: University of Oxford

Clinical PhD Programme at the University of Oxford: 'The identification of autoimmune susceptibility genes using ENU mutagenesis.' 31 Aug 2010

The identification of autoimmune susceptibility genes using ENU mutagenesis The aim of this project is to advance the understanding of basic mechanisms in autoimmunity by studying ENU mouse strains that have a defective immune response to self-antigens. In order to increase the yield of autoimmune phenotypes in the inbred ENU pedigrees, a sensitized screen has recently been developed using the Y chromosome autoimmune accelerator (Yaa) introduced to the C57BL/6 (B6) mouse. The aim of this studentship will be: (i) to characterise Yaa strains that develop heritable systemic autoimmunity ? anticipated to be marked by antinuclear antibodies, immune complex formation and renal disease. (ii) To identify the causative mutations by mapping and sequencing using high throughput whole genome analysis and matching to reference genome. To develop a pipeline for sequencing that will reduce dependence on mapping. (iii) Combine the functional and genetic knowledge in order to understand new mechanisms of pathogenesis and normal regulation; this will involve in vitro and in vivo methods for studying gene function and expression. (iv) Relate the findings to human disease and models of self tolerance. The project will provide training in basic immunology and a wide range of laboratory techniques, as well as renal histopathology and sequencing work.

Amount: £282,300
Funder: The Wellcome Trust
Recipient: University of Oxford

Integrated studies of the targets, regulation and consequences of human immunity to malaria. 08 Jul 2010

This proposal seeks support for an epidemiological and analytical framework developed by us over a number of years in Kilifi, Kenya. Specific elements include longitudinal monitoring of four cohorts of children with detection and careful phenotyping of clinical events in order to relate putative immune functions to immune status. It also includes a carefully documented historical archive of parasite and human samples allowing us to examine the population level consequences of changes in immun ity. Within this framework we will focus on (1) identifying immune targets on the merozoite by using sera of carefully defined immune status to probe both 2D gels and libraries of expressed merozoite proteins; (2) characterizing parasite-derived antigens on the surface of the infected red cell associated with low immunity and virulence; (3) identifying the mechanisms regulating the immune response to malaria; (4) determining which non-antigen genes are subject to immune selection through w hole-transcriptome and whole-genome comparisons of P. falciparum parasites from populations that have been under different intensities of immune selection pressure over a long period of time; and (5) determining the effects of changing transmission on human and parasite populations by a combination of mathematical modelling and next-generation parasite sequencing.

Amount: £1,499,726
Funder: The Wellcome Trust
Recipient: University of Oxford

Selfish mutations in the testis: impact on evolution and disease. 22 Apr 2010

The specific aims of this application are to: 1. Explore further our proposal that signalling through RAS is a critical mediator of paternal age effect mutations, and to elucidate the downstream pathway(s) involved, we will develop reliable assays for mutation hotspots in HRAS and downstream effectors (BRAF, MEK1/2, PI3K and AKT), in sperm. 2. Ask how levels of selected mutations change in frequency with donor age, using a panel of samples already collected for the purpose. This will enable us to model the evolution of individual clonal mutational events. 3. Develop computational methods to identify putative signatures of recurrent mutation in the human genome (through breakdown of linkage disequilibrium), and test experimentally whether these predicted sites show increased mutation levels in sperm. 4. Detect these clonal mutational events in normal testes by visualizing alterations in staining pattern (using spermatogonia-specific immunohistochemical markers), followed by microdis section and mutation analysis to explore their genetic basis. 5. Develop genome-wide approaches to the detection and measurement of sites that are subject to elevated mutation levels in sperm. 6. Compare our experimental findings with outputs from individual genome sequencing projects.

Amount: £1,135,718
Funder: The Wellcome Trust
Recipient: University of Oxford

Supplementary funding 29 Mar 2010

Elevated plasma levels of fibrinogen have been shown to be an independent risk factor for ischaemic heart disease and have also been associated with other thrombotic disorders such as stroke, peripheral arterial disease and venous thrombosis. This risk may be mediated in part via altered fibrin structure as we have demonstrated in myocardial infection (MI) patients and their first-degree relatives (Mills et al, Circulation, in press 2002). The fibrinogen gene transcript is processed by alternative mRNA splicing resulting in a variant of the gA/gA chain of fibrinogen denoted gA/g'. This gA/g' variant has 4 amino acids deleted from the carboxy-terminus of the gA/gA chain of fibrinogen which is substituted with a 20 amino acid extension. It has recently been shown that g' binds factor XIII (FXIII) and thrombin and also enhances activation of FXIII by thrombin. Activated FXIII cross-links fibrin polymers to form fibrin clot structures that are more stable physically and chemically, and it has been demonstrated that clots prepared using gA/g' rather than gA/gA fibrinogen have greater resistance to fibrinolysis. The presence of gA/g' is thought to occur as approximately 10-15% of total fibrinogen within normal individuals. Most recently it has been possible to measure gA/g' levels in plasma and it has been shown that patients with coronary artery disease have elevated gA/g' levels, independent of total fibrinogen level. The variation of gA/g' plasma levels in subjects with other thrombotic disorders is unknown. We will therefore develop and characterise an ELISA specific for gA/g' fibrinogen and using this ELISA determine gA/g' levels in patients with various thrombotic disorders (i.e. patients that have had myocardial infarction, stroke, venous thromboembolism and first-degree relatives of MI patients). We will also use a family study of 539 subjects of which there are 89 pedigrees to assess heritability of gA/g' levels using genetic model fitting techniques. Furthermore we will study the effect of varying gA/g' levels on ex-vivo fibrin structure.

Amount: £55,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Generation of an antibody library against transcription factors. 31 Aug 2010

Adapting specific anti-peptide phage combinatorial library technology to a peptide capture phage assay in generating anti-transcription factor antibodies

Amount: £128,750
Funder: The Wellcome Trust
Recipient: University of Oxford

Neural signals for expectation and surprise in human visual cortex. 01 Jul 2010

Remarkably little is known about how (i) neural responses generated by the expectation of a percept, and (ii) the surprise responses that occur when that expectation is violated, contribute to visual perception. Here, we use a combination of computational modeling techniques and functional brain imaging to test the view that expectations are 'subtracted' from visual inputs, such that bottom-up, evoked responses correspond to 'prediction error' signals. Our approach to this question includes (i ) assessing the mean impact of expectation and suprise on fMRI signals in the extrastriate visual cortex, and asking whether they activate distinct patterns of voxels; (ii) testing whether surprise responses are sensitive to information about the statistical patterns of information in the environment (e.g. volatility, or entropy), to demonstrate that visual surprise reflects more than a release from neuronal fatigue; and (iii) measuring surprise responses to percepts rendered undetectable by mas king to test whether they depends on conscious attention or updating mechanisms.

Amount: £242,711
Funder: The Wellcome Trust
Recipient: University of Oxford

Does inhibition of PIM kinase represent a novel mechanism to regulate the activity of ABCG2?. 06 Oct 2009

ABC efflux pumps such as ABCG2 play an important role in treatment success in several diseases including cancer, where they can confer resistance to chemotherapy. ABCG2 is also expressed in healthy tissues and therefore influences pharmacokinetic profiles of drugs in the body. Consequently, a great deal of effort has been directed towards generating drugs capable of inhibiting efflux pumps. Unfortunately, this strategy has been unsuccessful due to factors such as (i) poor understanding of the dr ug-pump interaction and (ii) poor selectivity of inhibitors to specific ABC proteins. Therefore, strategies involving modulation of expression, or cellular regulation, of pump activity have been explored. Recently the serine/threonine kinase Pim-1 has been demonstrated to modulate ABCG2 mediated resistance; thereby suggesting that the kinase acts as a regulatory protein. Our aim is to describe how phosphorylation by Pim-1 modulates ABCG2 activity. Our strategy will utilise purified proteins and systems have already been developed to enable this molecular strategy. The investigations will also provide proof-of-principle for restoration of sensitivity to chemotherapy by the novel strategy of inhibiting a regulator of ABCG2 activity.

Amount: £168,220
Funder: The Wellcome Trust
Recipient: University of Oxford

Timing expectations in the human brain. 08 Oct 2009

We have come to understand that perception is a highly proactive process, biased to deliver the events that are most relevant to our current motivational state and task goals. Attention research has shown how signals coding predictions about the location, identity or simple features of relevant events can influence several stages of neural processing. Though expectations about the timing of events are also pervasive, the temporal dimension has been left out of mainstream research. The experiment s proposed redress this imbalance by investigating the neural systems and neural mechanisms by which temporal expectation modulates information processing and influences top-down modulation by other types of attention. In order to understand whether temporal expectation operates through a modality-independent set of mechanisms, direct comparisons will be made between effects within the visual and auditory modalities, as well as across modalities. Nine experiments are proposed, using systematic m anipulations of temporal and other types of expectations (Series 1) and of sensory modalities (Series 2). In order to reveal the neural systems and mechanisms with high spatial and temporal resolution, and to test for their causal role; the methodology includes complementary hemodynamic (fMRI) and magneto/electrophysiological (MEG/EEG) brain-imaging methods, complemented by non-invasive transcranial magnetic stimulation (TMS).

Amount: £243,590
Funder: The Wellcome Trust
Recipient: University of Oxford

The role of the von Hippel-Lindau Hypoxia-inducible factor (VHL-HIF) pathway in cardiac and skeletal muscle energetics. 03 Dec 2009

This project aims to investigate the metabolic phenotype in mice engineered to have the Chuvash Polycythemia mutation. This is interesting because the Chuvash mutation causes a modest elevation in the hypoxia inducible factor family of transcription factors, and this enables us to study the effects of hypoxia signalling on metabolism without the confounding influence of actual periods of low oxygen availability. As yet unpublished observations in humans have shown a profound effect of Chuvash po lycythemia on metabolism which requires further dissection in an animal model. Our specific aims are: a) to establish whether a similar phenotype exists in the mice; b) to determine whether the predicted alterations in enzyme concentrations/activities occur in these mice; c) to determine whether there is a significant alteration of pyruvate metabolism (with a switch away from entry to the TCA cycle towards lactate production) and d) to determine whether the substrate switching observed in the fa iling (chronically hypoxic) heart is also induced in these mice. The results from these studies should provide some fundamental insights into the regulation of metabolism together with a better understanding of the degree to which alterations in HIF may underlie the metabolic changes in the failing heart.

Amount: £216,547
Funder: The Wellcome Trust
Recipient: University of Oxford