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University of Oxford

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Student electives for Gina Hadley, Clare Webb, Zoeb Jiwaji, Emily Parker and Jonarthan Thevanayagam. 18 Jul 2007

Malaria is one of the deadliest infectious parasitic diseases. Combination therapy, which has already been introduced in Kenya may not address the problem of the ability of the parasite to quickly select for resistance against antimalarial drugs, due to the detrimental effect of disparate pharmacokinetic profiles of drugs used. Strategies have to be devised to tackle the drug resistance. One such strategy is to predict and monitor the emergence and the spread of drug resistance parasite before drug resistance become s a problem. As Co-artem® has already been introduced in Kenya, the information that this project will provide is vital.

Amount: £5,600
Funder: The Wellcome Trust
Recipient: University of Oxford

Value in People award. 18 Jul 2007

Not available

Amount: £300,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Administrative meeting in Kilifi - 18 to 20 September 19 Jul 2006

The Wellcome Trust Centre for Research in Clinical Tropical Medicine, University of Oxford, proposes to continue its role in coordinating and facilitating the large programme of research carried out by the Oxford Tropical Network. This programme aims to improve the prevention, diagnosis and management of important tropical diseases through a better understanding of their pathogenesis, pathophysiology, genetics and epidemiology and the development of new treatments and vaccines. The main areas of interest are the major infectious diseases causes of morbidity and mortality in the developing world; malaria, pneumococcal disease, tuberculosis, HIV associated opportunistic infections , melioidosis, typhoid, tetanus, rickettsial diseases, dengue and viral encephalitides, as well as emergent western diseases such as hypertension and type II diabetes mellitus, thalassaemias and non-infectious problems such as poisoning and envenomation. As in previous years related basic science research will be carried out in the Nuffield Department of Clinical Medicine, the University Department of Paediatrics, and the Institute of Molecular Medicine, in support of epidemiological and clinical investigations in the Oxford-linked Wellcome Trust Tropical Units in Thailand, Viet Nam and Kenya and other overseas investigators and collaborators. Close links will be developed with the department of Public Health. The main role of the Oxford Centre is to provide administrative and logistic support for the overseas units and to identify, recruit, encourage and support the training of outstanding young clinical scientists in Oxford and in its linked tropical units. Continuing support for the Oxford Centre is justified by the achievements of the Oxford Tropical Network which, over the past five years, has yielded more than 400 peer-reviewed publications which have been influential in changing health policy and medical practice, and has trained 22 young medical scientists.

Amount: £5,550
Funder: The Wellcome Trust
Recipient: University of Oxford

A behavioural model of bilateral cochlear implantation. 12 Jul 2006

Unilateral cochlear implantation (CI) restores partial hearing to patients: they often understand speech, but only in quiet conditions, and have severe sound localization deficits. Normal listeners hear speech-in-noise and localize sounds better with two ears, utilizing interaural level differences (ILDs) and interaural time-delays (ITDs). For these reasons, bilateral CI has been trialled. Bilateral implantees show improved localization and ILD sensitivity, but moderate ITD thresholds, with highly variable results. Effects of auditory experience, age at hearing loss or deafness duration may account for this variability. We have developed an animal model of bilateral CI, with the aim of maximizing binaural benefits of CI in humans, whilst utilizing CI as a tool to study the development and plasticity of the neural mechanisms underlying binaural processing. Ferrets will be deafened, bilaterally implanted and chronically stimulated in infancy. Once they are mature, we will assess their ability to localize sound and to process binaural cues using behavioural and electrophysiological techniques that are currently in use in this laboratory. We will then examine the effects of age at hearing loss and duration of deafness on the development of these measures. Lastly, potential benefits of auditory training and an experimental processing strategy, designed to better-preserve ITD cues, will be assessed.

Amount: £738,458
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural and biophysical studies of dengue virus neutralization and infection enhancment by monoclonal antibodies. 12 Jun 2006

Structural and biophysical studies of dengue virus neutralization and infection enhancement by monoclonal antibodies The mechanisms of antibody-dependant neutralization and enhancement of dengue virus infection by monoclonal antibodies are very poorly understood. Mechanisms for neutralization have been proposed based on antibodies either blocking virus attachment to receptor and/or inhibition of conformational change required for viral fusion, whereas it has been postulated that the mechanism of enhancement is dependent on weak antibody binding that is insufficient to neutralize. A structural analysis of the interaction of the envelope protein of dengue virus with various antibodies of different neutralization activity, antigen specificity and avidity, is important to be able to correlate structural and biophysical data with function. This is fundamental if one is to gain an understanding of the fundamental basis for antibody neutralization and enhancement, and will impact on the design of future vaccines for dengue. The goal is a structural characterization of the interaction between the envelope glycoprotein (E) of dengue virus with functionally well characterized antibodies, in order to tease out if there are generic mechanisms for neutralization and enhancement. 1. Determine the structure of complexes of domain III of E with antibodies of known serological properties. 2. Determine the structure of complexes of full length E with antibodies of known serological properties. 3. To biophysically characterize the interaction of these antibodies with E using techniques, such as SPR and AUC. The effects of pH on antibody binding will be examined as well as the effects of binding to potential receptors. 4. To determine the structure of virus-Fab complexes either by cryo-electron microscopy or crystallography.

Amount: £138,215
Funder: The Wellcome Trust
Recipient: University of Oxford

The role of local network activity in stimulus-induced direction selectivity. 10 May 2006

The project will investigate how local network activity helps to shape stimulus-induced changes in the functional properties of sensory neurons. The general aim is to elucidate the role of local glutamate and _-aminobutyric acid (GABA) mediated signals in the stimulus driven physiological changes that occur in a developing visual system. The research will focus on direction selectivity in the retinotectal system of Xenopus Laevis tadpoles. This system represents the Xenopus' primary pathway, where axons from the retinal ganglion cells in the ye project to the brain and form glutamatergic synaptic connections on the dendrites of optic tectum neurons. Direction selectivity in tectal cells can be rapidly induced by training, and tectal cells are known to be very sensitive to spatiotemporal statistics in visual stimuli.

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

The molecular and functional effects of Type II metabotropic glutamate receptor (GRM2/3) gene deletion in the mouse brain. 23 Jan 2006

The molecular and functional effects of Type II metabotropic glutamate receptor (GRM2/3) gene deletion in the mouse brain To characterise the molecular and functional profiles of GRM2/3 double knockout mice. This will be achieved by the following objectives: 1) Evaluating the expression of genes relevant to glutamate neurotransmission (e.g. glutamate transporters and NMDA receptors) in the brains of GRM2/3 double knockout mice; 2) Measuring long-term potentiation (LTP) and pre-synaptic activity in the hippocampus of experimental animals and controls; 3) Examining spatial working/reference memory, anxiety and locomotion in GRM2/3 double knockout mice and controls.

Amount: £11,970
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

Role of KATP-channels in the control of glucagon secretion from human and rodent pancreatic islets. 11 Jul 2006

The control of glucagon secretion from the a-cells of the pancreatic islets ispoorly understood. Both paracrine (due to substances released from neighbouring cells) as well as intrinsic processes (i.e. within the a-cell itself) have been proposed to be of importance. Here we shall apply a combination of biochemical measurements of glucagon release, biophysical experiments (patch-clamp and capacitance measurements) and confocal [Ca2+]i-imaging to rodent and human pancreatic islets. We shall: 1) test the hypothesis that the intrinsic regulation of glucagon secretion depends on closure of a-cell KATP-channels; 2) establish the ion channel complement of the a-cell, which determines the electrical as well as secretory responses to the membrane depolarization resulting from closure of the KATP-channels; 3) assess the importance of the intrinsic mechanism(s) vs. paracrine processes inthe control of glucagon secretion by experimental interference with critical signalling pathways (e.g. insulin, somatostatin, Zn2+, GABA); and 4) investigate the relative roles of KATP-channels and the cAMP effector proteinsPKA and cAMP-GEFII in the modulation of glucagon secretion by adrenaline and GLP-1; both agonists acts by increasing cAMP and yet they have opposite effects (stimulation by adrenaline and inhibition by GLP-1) on glucagon secretion.

Amount: £196,104
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

Cognitive systems in the brain: modelling invariant object recognition in natural visual environments. 27 Feb 2006

We will build on recent neurophysiological discoveries on inferior temporal visual cortex neuronal activity to develop understanding at the computational neuroscience level of the mechanisms that underlie our ability to recognise objects in natural scenes, independently of their view, size, and exact position. Novel goals include: 1. We will incorporate our discoveries on the receptive fields of neurons in natural scenes into a refined model to show howinvariances can be learned, and how multiple objects can be recognised, in natural scenes. 2. We will incorporate a new 'continuous transformation' mechanism for invariance learning that we have recently discovered. 3. Becausethe spatio-temporal statistics of the world interact with the functional architecture and dynamics of the visual system, we will use 3D modelling toolsto generate training images with spatio-temporal statistics that are quantitatively defined but also increasingly approach those present when natural scenes are viewed. 4. We will correspondingly add realistic dynamics to the system by introducing integrate-and-fire neurons to some simulations.

Amount: £191,564
Funder: The Wellcome Trust
Recipient: University of Oxford

Functional characteristics and associated structural features of mammalian melanopsin photopigments 27 Apr 2006

Melanopsin (a member of the opsin family of G protein coupled receptors) is thought to be the photopigment of recently discovered inner retinal photoreceptors in mammals. To allow direct functional analysis of this protein we have lately developed methods for its heterologous expression in cell culture and shown that, under these conditions, it binds retinal to form a photosensory complex with the ability to regulate cell activity via G-protein signalling. Here we propose building on our heterologous expression breakthrough to conclude a detailed functional and structural analysis of this protein based around 3 goals.Goal 1. To consolidate our functional analysis of human and mouse melanopsins using spectroscopic, physiological and biochemical approaches to elucidate aspects of its photochemistry (especially its spectral sensitivity and photoactivation) and G protein coupling.Goal 2. To generate an accurate 3D structure of melanopsin, based initially upon an empirical computer model, and refined according to experimental examination (cf goal 3) and 2D/3D crystallography.Goal 3. To establish critical structure:function relationships for melanopsin by using our developing structural understanding to define suitable site directed mutants and exposing them to detailed functional analysis.

Amount: £73,220
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

Proliferation and death of T-cell subsets following vaccination. 12 Jul 2006

The kinetics of T-cell proliferation and death following vaccination in humansare poorly understood. There is an immense effort underway to develop a new generation of vaccines to generate protective T-cell responses against a number of key pathogens responsible for morbidity and mortality on a massive scale. A greater understanding of the processes that lead to effective and durable memory could have a major impact on the design of new vaccines and theimmunization regimes, perhaps allowing development of new adjuvants that enhance survival of memory T-cells following the initial 'burst' response.Labelling dividing cells with deuterium presents a new, safe, radiation-free method of measuring kinetics of antigen-specific T-cells and their subsets. I propose to use this technique to measure T cell responses induced by the tuberculosis vaccine MVA85A in eight healthy BCG-primed volunteers.I will also study apoptosis of vaccine-induced T cells following vaccination with new malaria and tuberculosis vaccines using an apoptosis assay and caspase activation assay. This research will utilise samples from twelve volunteers in upcoming studies in the Oxford clinical trials programme.I also plan to use anti-apoptotic agents in vitro to try modifying this process to increase the size of the resulting memory pool.

Amount: £242,111
Funder: The Wellcome Trust
Recipient: University of Oxford

Initiation and impact of conjugative transfer by antibiotic resistant haemophilus element. 06 Dec 2005

The spread of antibiotic resistance is a major threat to the continued successof medicine. By studying the evolution and properties of antibiotic resistancein Haemophilus influenzae, which arises from the successful spread of a singlefamily of conjugating and integrating elements (ICEs) world wide, an explanatory model is possible. Furthermore, these ICEs are evolutionarily related to a number of well known pathogenicity islands. This provides a research opportunity for testing widely held hypotheses about the emergence and spread of antibiotic resistance or genomic islands. The proposed training fellowship aims to contribute to this by investigating first the initiation ofconjugation by ICEs and second provide proof in principle that these ICEs may contribute to the diversity in H. influenzae by the following approaches:1. The oriT of ICEHin1056 will be identified and characterised. The role of traI and its regulation will be studied using a combination of cloning, mutagenesisand transcriptional analysis using microarrays. 2. The role of ICEs in the genetic diversification of H. influenzae will be studied by determining sequence variation in divergent sequences close to the putative oriT. The ability of ICEs to mobilise whole chromosomes in an Hfr-like mechanism will also be investigated.

Amount: £211,276
Funder: The Wellcome Trust
Recipient: University of Oxford

Cellular immune responses in children with Plasmodium falciparum infection. 23 Mar 2006

he diversity of Plasmodium falciparum isolates is an important determinant of the heterogeneity in clinical malaria. Many targets of the humoral immune response are polymorphic or undergo antigenic variation. Clinical immunity maybe the result of cumulative acquisition of a diverse antibody repertoire. Antibody responses to a variety of malarial antigens are short-lived and detectable only during asymptomatic infection. However, the cellular mechanisms determining the nature of antibody responses in P. falciparum infection are not understood. One family of variant proteins, the P. falciparum erythrocyte membrane protein-1 (PfEMP-1) mediates adhesion of bloodstage parasites to host cells. Cytoadhesion is associated with (i) pathology, (ii) immune selection, and (iii) immune deviation. I have shown that cytoadhesion of parasites to CD36 modulates dendritic cell function in vitro and systemic cytokine responses in vivo. I now propose to determine the relationship between the phenotype of parasite isolates and the immune responses to PfEMP-1 and how this relationship evolves with exposure. I will define:(i) Whether there are differences in cellular immune responses to PfEMP-1 dependent on the adhesion phenotype of the parasite isolate.(ii) The cellular mechanisms underlying the evolution of unique and cross-reactive antibody responses to PfEMP-1 during the natural history of infection.

Amount: £1,291,901
Funder: The Wellcome Trust
Recipient: University of Oxford

Choose a life. Choose your life. Choose Life? Bioethical issues at the beginning, middle and end of life. 22 May 2006

Choose a Life. Choose Your Life. Choose Life? Bioethical Issues at the Beginning, Middle and End of Life The symposium will have three sessions, arranged around the bioethical issues at the beginning, middle and end of life. The first session will examine reproductive ethics issues and concerns about the use of embryos. The second, issues raised by genetic testing and the use and storage of genetic information. The final session will cover end-of-life and terminal care issues. Medicine focuses on the physiology of the body, but cannot give satisfactory answers to bioethical and metaphysical questions that arise as we make decisions about how to treat and how to live. Humanities deals with these questions, but does not always the have capacity to understand the practical and scientific issues involved in these decisions. The interdisciplinary field of Medial Humanities seeks to draw together researchers from the medical sciences and the humanities in a dialogue about how these questions can be answered in a more holistic, and hence more satisfactory way. Given the inherent divisions between the disciplines that fall under the heading 'medical humanities', researchers in these diverse fields often will not be fully aware of how relevant work done in other fields and from other perspectives. In many instances, researchers may be working in parallel with one another but rarely come into contact with one another. There is hence a need for communication between these disciplines, and particular the provision of forums that facilitate conversation in shared issues between members of these different fields. This gathering will broaden the dialogue and actively bring into the conversation these other fields - medical anthropology, history of medicine and theology. While there are many conferences that cover issues raised by embryo research, genetics and end-of-life decision-making, these are usually targeted at ethicists, clinicians and lawyers. This gathering is needed, as it will invite speakers from these other disciplines, to engage in discussion on these issues about life and life choices.

Amount: £1,910
Funder: The Wellcome Trust
Recipient: University of Oxford

Nuclear magnetic resonance spectroscopy as a tool to study the structure, function, dynamics and folding of proteins: University Award for a research technologist in biomolecular NMR. 21 Feb 2006

The key goal of this proposal is to identify ways in which state-of-the-art NMTo characterise the structure, dynamics and Ca2+-binding properties of cbEGF dTo understand the importance of the covalently bound heme in c-type cytochromeTo characterise the structure, dynamics and interactions of the redox protein To characterise the structure, dynamics and ligand-binding properties of proka

Amount: £303,200
Funder: The Wellcome Trust
Recipient: University of Oxford

Open access award. 20 Sep 2011

Not available

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford