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Recipients:
University of Oxford

Results

The role of chloride regulation in epilepsy. 10 May 2006

In both human cases of epilepsy, and in animal models, seizure activity has been shown to lead to abnormal neuronal morphology and connectivity. For example, the inducement of epileptic-like activity in the rat hippocampus leads to a decrease in the density of dendritic spines within pyramidal neurons of around 20-40%. Tissue samples taken from temporal lobe epileptic patients also reveal significant atrophy of the neocortical grey matter with pyramidal cells possessing sparser dendritic trees and reduced spinie density compared to age-matched controls. Such patho-morphological changes are believed to have important consequences with regards to normal neuronal function and may lead to increased susceptibility and likelihood of future epileptic insults. The cellular processes behind these changes are poorly understood and any insights would help to elucidate the mechanisms by which epileptic states are initiated and maintained within neuronal tissue, as well as potentially providing novel therapeutic targets and approaches to treating the disorder.

Amount: £141,236
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £141,236
Funder: The Wellcome Trust
Recipient: University of Oxford

The Endurance of the Carrier Narrative: 'Patient Zero', Gaetan Dugas, and the Assignment of Blame in Epidemics. 14 Jun 2006

The proposed research intends to establish the origins of the 'patient zero' concept, account for the means of its rapid cultural diffusion, and locate it within a wider historical framework. The project has four key goals. First, it aims to reconstruct the events culminating in the early 1980s epidemiological cluster study that first posited the significance of a 'patient zero'. Second, the extent to which key players, including public health officials, Randy Shilts, the news media, and the entertainment industry, were each responsible for the promotion of the 'patient zero' character will be determined. Third, efforts will be made to reconstruct Gaetan Dugas's experience as a patient, from archival research and interviews with his acquaintances, his doctors, and the public health officials who met with him. Finally, the project aims to demonstrate the cyclical nature of the 'healthy carrier' narrative underlying the 'patient zero' concept. In this regard, the project will consider the treatment, by both the media and public health officials, of Gaetan Dugas in relation to that of 'Typhoid' Mary Mallon. Newly released testimonies from the Krever Inquiry into the contamination of the Canadian blood industry will also be examined as a more recent recurrence of the narrative.

Amount: £79,234
Funder: The Wellcome Trust
Recipient: University of Oxford

Malaria burden and control at national, regional and global scales. 22 Jun 2006

The work in this application will provide the most complete understanding of the spatial distributions of malaria risk at national, continental and global scales since the 1960's. The approach will allow for a transparent, evidence-driven estimation of the public health burden posed by the malaria parasite and its diversity in space and time. The epidemiological platform will provide the means to articulate needs and model the impact of changing demographics, climate, poverty and intervention between 2005 and 2030. Effective control, however, will be predicated on a number of operational constraints which must be defined and understood to ensure that patients and communities most in need have access to interventions that work. How well interventions are delivered at national scales is the subject of a complementary programme of research: providing the link between the theoretical impacts of disease control and the likely operational efficiency of interventions when delivered as part of national policies in Africa.

Amount: £3,416,292
Funder: The Wellcome Trust
Recipient: University of Oxford

Transdiagnostic cognitive behaviour therapy for eating disorders: efficacy and mechanisms of action. 22 Jun 2006

Clinical eating disorders such as anorexia nervosa and bulimia nervosa are a cause of substantial physical and psychosocial morbidity. They typically begin in adolescence and often run a chronic course. They are difficult to treat and they impose a significant burden on health services. This application is for funds to continue a long-term, Trust-funded, programme of research on these disorders and their treatment. One major outcome of this research has been the development of the leading evidence-based treatment for eating disorders (cognitive behaviour therapy for bulimia nervosa), a treatment strongly endorsed by NICE and other national clinical practice guidelines. Recently we have developed an "enhanced" theory-driven form of this treatment (CBT-E) that is designed to be suitable for the full range of eating disorders seen in clinical practice, rather than just cases of bulimia nervosa. Our data suggest that CBT-E is a potent treatment for the majority of these patients. We now propose to study: 1) whether CBT-E operates through mechanisms that are specific to it; 2) whether CBT-E is clinically superior to the leading potential alternative treatment; 3) how CBT-E is likely to work; 4) the utility of CBT-E in treating those patients who are severely underweight.

Amount: £3,974,171
Funder: The Wellcome Trust
Recipient: University of Oxford

Transcription termination: interconnections between transcription and pre-mRNA processing. 17 Oct 2005

All stages of gene expression from nuclear transcription to cytoplasmic translation are intimately connected. We demonstrated two decades ago that the pre-mRNA processing reaction of 3' end cleavage/polyadenylation connects to transcription elongation/ termination. Since then all mRNA processing reactions have been shown to occur co-transcriptionally, affording tight gene regulation. We will extend our understanding of these connections to an advanced stage. We aim to determine how the chromatin template influences the connection between transcription and mRNA processing. We will then concentrate on dissecting the different ways transcription termination occurs in both yeast and mammalian genes. We will also extend our understanding of how termination feeds back to reinitiation of transcription by analysis of recently discovered gene loops. Our approach of comparing the mechanism of RNA polymerase I and II transcriptional termination in yeast as well as comparing RNA polymerase II termination between yeast and mammalian cells has already generated new data (see Appendix Figure 1-5). We now plan to fully dissect the molecular mechanism and biological significance of eukaryotic transcriptional termination. As such we are investigating fundamental aspects of eukaryotic gene expression, an essential approach to interpret the significance of the human genome sequence.

Amount: £1,853,834
Funder: The Wellcome Trust
Recipient: University of Oxford

Supplement for Laos Infectious Disease Building. 30 Aug 2006

The research conducted by the Thailand-based clinical research programme has changed the treatment of both severe and uncomplicated malaria, and melioidosis. The central aim of this proposal is to develop and evaluate effective and practical means of diagnosing, treating, and, if possible, preventing the main tropical diseases responsible for significant morbidity and mortality in rural areas of Southern and Eastern Asia. These are malaria (P. falciparum, P. vivax, and severe infections), melioidosis, leptospirosis, cryptococcal meningitis, pneumococcal disease in infancy, enteric fever, rickettsial diseases, infantile beriberi, and the burgeoning problem of counterfeit anti-infective drugs. Integrated epidemiology, field based studies of pathophysiology and pharmacology, diagnostics, clinical trials, laboratory research, and innovative approaches to analysis will be combined. This will also provide a platform for regional capacity building and training. We are confident we can achieve our main objective of providing achievable and measurable methods of improving the health outcomes of these major diseases within the five year programme.

Amount: £219,771
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural studies of the paxillin interaction network and its role in focal adhesion dynamics and signalling. 27 Apr 2006

We propose to extend our recent structural studies (Arold et al., 2002; Hoellerer et al., 2003) to generate a dynamic picture of the interactions of the focal adhesion (FA) proteins FAK, ILK and actopaxin with the adaptor protein paxillin. We will define the role these interactions play in recruitment and activation of proteins to FAs as well as their eventual exclusion during FA disassembly. This picture will be developed at resolutionsthat extend from the atomic to the cellular level. Atomic details will be provided by NMR and X-ray crystallographic imaging of individual functional domains in complex with different binding partners. Molecular interactions will be characterised by studying binding events by NMR, isothermal titration calorimetry and surface plasmon resonance, using different fragments of FAK, ILK, actopaxin, paxillin, and GRB2. In particular, we will define which interactions are mutually permissive or mutually exclusive, how they are affected by phosphorylation, and we will seek to relate this information to the dynamic process of FA turnover. Models of molecular interactions developedthrough these studies will be tested in a cellular context by expression of suitable constructs in cultured cells, followed by fluorescent microscopy and cell adhesion and migration studies.

Amount: £200,690
Funder: The Wellcome Trust
Recipient: University of Oxford

Developmental trajectories of unimodal and cross-modal attention deficits: the case of fragile X syndrome. 10 May 2006

Fragile X syndrome (FXS) is caused by the silencing of a single gene affectingmultiple aspects of cortical development. In late childhood and adulthood, FXSis associated with striking inattention and hyperactivity. Our previous work revealed attentional deficits in toddlers and infants with FXS, highlighting very early onset of difficulties. Hitherto, deficits have been investigated using visual stimuli, but clinical evidence points to difficulties in other modalities, such as audition. Critically, attentional deficits in FXS may be exacerbated by the requirement of selecting multimodal real-world stimuli. Theprimary aim of the current proposal is therefore to investigate the impact of FXS on early developmental trajectories of visual and, for the first time, auditory and crossmodal attention, combining genetics, cognitive developmentaland psychophysical methods. More specifically, we aim to test the following hypotheses: i) developmental trajectories of unimodal and crossmodal attentionin fragile X syndrome will increasingly deviate from normal over early childhood (Goal A); ii) tasks resulting in conflict across modalities will

Amount: £341,196
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural studies of the human Notch-1 ligand-binding region. 21 Feb 2006

During development it is essential that cells are guided to their correct location within the embryo and that they differentiate into the appropriate cell type. A key short-range signal which has been highly conserved during metazoan evolution involves the Notch receptor which regulates spatial patterning, timing and outcomes of numerous cell fate decisions. A structural understanding of the Notch receptor -ligand interaction, which is currently lacking, would greatly enhance our understanding of the signalling mechanism and may lead to the design of novel agonists and antagonists of the receptor. With the current interest in cell-based therapies, manipulation of the Notch signal represents a promising strategy to produce defined cell types in vitro for therapeutic use. In this application we aim to i) crystallise and determine the individual atomic structures of the ligand binding region of human Notch-1 (hN-1) and the receptor binding portions of its ligands human Delta-like 1 and human Jagged-1 ii) identify the structural basis for the observed inhibitory effect of hN-1 EGF10 on ligand binding and the mechanism by which post-translational modification overcomes this effect iii) identify the stability of a Notch-ligand complex by SPR, and determine its atomic structure by X-ray crystallography and/or NMR shift mapping.

Amount: £184,579
Funder: The Wellcome Trust
Recipient: University of Oxford

Premotor networks in the human brain: anatomy, physiology and modulation in disease. 13 Dec 2005

This project aims to develop novel neurorehabilitation strategies to promote motor recovery after stroke. It is focused on the human premotor cortex (PMC), a region shown to be critically involved in recovery of movement ability after stroke. I propose to study the anatomy, physiology and functional connectivity of PMC circuits in the healthy human brain, to test for changes in these circuits after stroke, and to assess the long term effects of modulating plasticity in PMC. My hypothesis is that by modulating activity in PMC we will enhance the effects of experience-dependent learning and plasticity in healthy controls and the beneficial effects of rehabilitative therapies in patients after stroke.In the process of addressing this clinical question I will also investigate the basic anatomy and physiology of PMC in the healthy brain. In particular, I will characterise the regional anatomy of the human premotor cortex using information on brain connectivity derived from diffusion MRI. Further, I will test the functional connections between PMC and other brain regions using paired-pulse TMS and FMRI - in particular to look for hemispheric dominance effects, changes in functional connectivity of PMC after stroke, and task-dependent modulations in PMC circuits.

Amount: £473,189
Funder: The Wellcome Trust
Recipient: University of Oxford

Corticostriatal control over hippocampal and amygdala-dependent appetitive learning and memory systems. 13 Dec 2005

There is growing evidence that multiple, interactive learning and memory systems provide the basis of behaviour, and that disruptions or imbalances within these systems result in the manifestation of abnormal behaviour. Considerable effort is currently being directed at characterising the key neural structures comprising these systems, and this project will investigate the neural and neurochemical basis of the competitive interaction between hippocampal and amygdala-dependent learning and memory processes in rodents, using a systems and multidisciplinary approach. I hypothesise that this interaction occurs in regions of the corticostriatal system that receive converging inputs from the HPC and amygdala, and is modulated by dopaminergic and glutamatergic systems. The first set of experiments will validate the causal roles of the ventral and dorsal HPC in appetitive conditioning and establish the functional connectivity of specific limbic-accumbens pathways using selective permanent or temporary lesions and electrophysiological recordings. The neural loci of interactions between HPC and BLA-mediated information processing will then be investigated using reversible inactivationand in vivo voltammetry targeting the prelimbic-infralimbic cortical regions, orbitofrontal cortex, and rostral pole of the NAc. Finally, the neurochemical mechanism of the competition will be established using intra-cerebral infusions of neuropharmacological agents manipulating the dopaminergic and glutamatergic systems.

Amount: £465,427
Funder: The Wellcome Trust
Recipient: University of Oxford

Slippery slopes in the history of in vitro fertilisation and therapeutic cloning: the influence of ethical argument on the development of law and policy. 26 Apr 2006

IVF and embryo research have been the subject of controversy for more than thirty years and have been attacked on the basis that allowing them is the beginning of a 'slippery slope' towards eugenics, state control of reproduction and reproductive cloning. Debates about these technologies have been characterised by fears of the 'uncontrollability' of science and the consequences of uncontrolled scientific development Robin Henig argues in her history of the reproductive revolution that many of the slipper slope ethical arguments initially raised against IVF are now being used against human cloning and genetic engineering. However, she points out that many of the predictions made in arguments have not occurred. This project will test this conclusion by examining the influence of slippery slope ethical arguments on the historical development of legislation regulating IVF - a technology that is now widely accepted - and therapeutic cloning technologies. The project will: Produce empirical findings on the influence of slippery slope arguments on policy development; Examine how slippery slope concerns in public and academic ethical discourses affect policy development; Compare the outcomes predicted in these arguments, with the actual outcomes of the development of these technologies to examine the concept of fallacy within slippery slope arguments; and Consider the ethical validity of resulting legislative measures given the actual outcomes.

Amount: £3,700
Funder: The Wellcome Trust
Recipient: University of Oxford

Phase II studies with MVA85A in Cape Town 12 Jun 2006

Summary not available

Amount: £75,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Student Elective Prize for Mr Adam Handel 29 Aug 2008

Magnetoencephalographic (MEG) study of facial pain

Amount: £1,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Value in People Award. 17 Oct 2007

Not available

Amount: £350,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Identification and functional analysis of susceptibility genes in multi- factorial diseases. 15 Apr 2008

The Wellcome Trust Centre for Human Genetics was established in 1994 to undertake research into the genetic basis of common diseases. The scientific objective of the Centre is to gain insight into mechanisms controlling genetic susceptibility to human disease including the localization and identification of disease genes, functional characterization of gene variants responsible for susceptibility, understanding how gene variants contribute to risk of disease in the population and how genetic factors contribute biologically to a disease process. In order to achieve this scientific objective the Centre's strategy was to bring together multidisciplinary research groups collaborating on human and rodent genetics, genetic epidemiology, functional analysis of disease genes, cell and developmental biology and structural biology. In addition, the Centre has a strong focus of expertise, equipment and resources centralized in Core groups allowing all research groups to benefit and expand their research strategies. The Core groups in Genomics, Molecular Cytogenetics and Microscopy, Bioinformatics and Statistical Genetics, and Transgenics provide first-rate services and perform research and development on new platform technologies as well as algorithms and databases needed to analyse complex datasets. This application is to continue our Centre status and provide funding for the running of these Core groups over the next five years.

Amount: £2,092,216
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigation into the functional role of ROR-gamma T in inflammatory bowel disease models. 29 Aug 2008

Mucosal immune responses are actively regulated to prevent development of harmful cell mediated immune responses, yet little is known about the cell types and cytokines involved in this regulation. Two broad approaches will be used to identify the basic mechanisms of mucosal immune regulation. In the first, a recently described murine model of colitis with similarities to Crohn's disease in man, which develops spontaneously in SCID mice restored with CD45RBhigh CD4+ T cells from normal donors and is completely prevented by co-transfer of the reciprocal CD45RBlow population, will be used to investigate mechanisms of disease induction and prevention. The mechanism of action of the regulatory CD45RBlow population will be dissected in vivo, including identification of immunosuppressive cytokines and their cellular source, which are critical for suppression of disease and effects of the CD45RBlow population on the homing properties of CD45RBhigh population. Experiments using gnotobiotic mice suggest components of the normal flora are involved in disease induction and these experiments will be extended to identify the antigen specificity of cells which cause disease and those that prevent it. The second approach will involve study of T-helper cell subset differentiation in the gastrointestinal tract in both tolerance and non-responsiveness. A TCR transgenic mouse line will be used to determine which T helper cell subsets are induced by oral tolerance regimes compared with oral immunisation and which cytokines are involved in the differentiation and effector functions of these cells. Recent evidence suggests that induction of TGF-ß and IL-10 producing regulatory cells may be an important component of oral tolerance. A genetic approach will be taken to allow the detection of IL-10 producing cells in vivo, providing information on the anatomical location of regulatory cells within the gut associated lymphoid tissue. The results of these experiments should define the rules that govern T helper cell subset differentiation in the gut, providing a basis for manipulation of T helper cell responses to ingested antigen. This may be particularly useful in a number of autoimmune diseases where induction of cells that suppress cell mediated immune responses is desirable.

Amount: £9,901
Funder: The Wellcome Trust
Recipient: University of Oxford

Contribution to the building costs of the Institute of Chromosome Biology. 19 Feb 2007

This proposal requests funds from the Wellcome Trust for the furbishment of an Institute of Chromosome Biology, which will be housed within the proposed new Department of Biochemistry building of the University of Oxford on South Parks Road. The Department is currently housed in four different buildings, most of which are antiquated and lack sufficient space and the facilities necessary to attract scientific talent at an international level. A new building will house most faculty, including several who work in chromosomes, as well as new professiorial appointments and research groups led by principal, senior, and career development research fellows, working on the replication, repair, recombination, segregation, transcription, and developmental potential of chromosomes. The new building will include facilities for computational biology, bioinformatics, proteomics, optical imaging, protein and nucleic acid analysis, structural biology, and single molecule analysis.

Amount: £6,271,731
Funder: The Wellcome Trust
Recipient: University of Oxford

Initiating Dissemination / Professional Engagement - Child & Newborn Health Group KEMRI / Wellcome Trust Programme, Nairobi. 18 Jun 2007

Our key goals in initiating a series of engagement activities are: 1) To host a joint Ministry of Health (MoH) / Child and Newborn Health (CNH) Group (KEMRI / Wellcome Trust) meeting to discuss early findings of attempts to introduce evidence based guidelines for care for sick children in hospitals and to report on lessons learned. 2) To host a Child and Newborn Health Group Conference with partners from the Ministry of Health, The University of Nairobi, The Kenya Paediatric Association and other medical training institutions to present research findings and discuss their implications for the future direction of and partnerships for research in these areas. 3) To survey medical trainees to establish their exposure to, access to and appreciation of research evidence. 4) To develop a pilot problem-based interface for medical trainees to illustrate the role and contribution of research to improving clinical care of the very sick child in low-income settings.

Amount: £19,738
Funder: The Wellcome Trust
Recipient: University of Oxford