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Recipients:
University of Oxford

Results

Sleep and Circadian Neuroscience Institute (SCNi) 17 Apr 2012

Sleep and circadian rhythm disruption (SCRD) is a clinically important feature of severe neuropsychiatric disorders, but it is rarely viewed as pathophysiologically significant, nor are its consequences appreciated or its treatment prioritised. However, emerging data challenge these assumptions, with increasing evidence that SCRD is important in illness onset, overall physical health and as a therapeutic target. Developments in circadian neuroscience now permit a meaningful scientific investigat ion of these important but neglected issues. Building upon our recent findings, and a unique breadth of expertise and shared interest, we propose to bring together molecular and systems neuroscientists, psychiatrists, psychologists, and bioengineers, to form a virtual Sleep and Circadian Neuroscience Institute (SCNi). We aim to: 1) Understand the causal relationships between SCRD and the psychoses, testing the hypothesis that pathways common to both account for the comorbidity, using preclin ical and clinical approaches. 2) Develop evidence-based interventions that correct SCRD and improve health. 3) Provide training and teaching materials in sleep/circadian neuroscience for psychiatry. 4) Disseminate research knowledge and treatment packages using web-based platforms. 5) Develop novel telemetric devices for home-based measurements of sleep and circadian physiology. SCNi will be truly multidisciplinary and translational, and will achieve these goals through five i nterlinked themes, described in Q10.

Amount: £4,434,125
Funder: The Wellcome Trust
Recipient: University of Oxford

Bacterial chromosome dynamics 04 Aug 2011

The objectives are to provide a comprehensive and integrated understanding of how the processes of DNA replication, recombination and chromosome segregation shape bacterial chromosome organization. Furthermore, the coordination between these processes with growth and cell division will be explored. The studies will use a combination of cellular in vivo studies and experiments in vitro that will help dissect molecular mechanism. Key goals. 1. To understand structure-mechanism-function relationshi ps in the DNA translocase FtsK; to gain insight into how FtsK activity is regulated at the molecular and cellular level; to understand how FtsK is organized in space and time within living cells; and to reveal what its precise biological functions in vivo are. 2. The gain further insight into the molecular mechanisms and biology of FtsK-XerCD-mediated chromosome dimer resolution and decatenation. 3. To understand how chromosome organization is shaped by replication-recombination-chromosome segre gation. 4. To gain insight into how MukBEF organizes bacterial DNA and to other processes involved in the organization and segregation of chromosomes.

Amount: £159,710
Funder: The Wellcome Trust
Recipient: University of Oxford

Purchase of electron microscopic infrastructure to establish a multi-user facility for cryo electron microscopy, in particular cryo electron tomography. 14 Oct 2010

The aim of this application is to obtain funds to contribute towards strengthening the infrastructure for 3D cryo electron microscopy and integrative microscopy across the University of Oxford. In addition to establishing the Oxford Particle Imaging Centre (OPIC) at the Division of Structural Biology (STRUBI), Wellcome Trust Centre for Human Genetics, as a state of the art multiuser facility for cryo electron tomography it will strengthen all three cryo electron microscopic imaging modalities, n amely electron tomography, 'single particle' analysis and 2D electron crystallography and will create a link to enable integrated multi-resolution structure determination including the unique super-resolution light microscopic techniques available in the Department of Biochemistry. By coordinating this effort with the Department of Biochemistry and the Dunn School of Pathology it will yield a new quality of interaction, communication and exchange in this field in Oxford. The combined facilities will provide the infrastructure to promote the analysis of pathogens-host interactions, large multi-protein macromolecular machines and membrane proteins that will be complementary to the local NMR and X-ray crystallography resources and also those available at the Diamond Light Source and the associated Research Complex.

Amount: £621,200
Funder: The Wellcome Trust
Recipient: University of Oxford

A Randomised, Open-Label, Comparative Study of Itraconazole vs Amphotericin B for the Induction Therapy of Penicilliosis. 16 May 2011

Penicilliosis is emerging as one of the three most common HIV-associated opportunistic infections in Asia.Despite the rapid growing HIV epidemics in a region that houses one half of the worlds population, there hasnot been a single randomised controlled trial to evaluate the treatment of penicilliosis. The currentrecommendation of amphotericin B for 2 weeks followed by itraconazole for 10 weeks is based on onenon-comparative study [1]. Amphotericin B has extremely limited availability, has significant side effects,needs to adminstered through a vein daily over 6 hours of infusion, and is prohibitively expensive in mostareas of Asia. Itraconazole, on the other hand, is widely available in local pharmacies throughout Asia, canbe given orally at a fraction of the price. Further, data from available case series suggest that itraconazoleand amphotericin B have similar efficacies. We therefore propose to conduct a randomised, open-label,non-inferiority trial of the efficacy of itraconazole versus amphotericin B for penicilliosis. 440 adults from inand outpatient settings with culture-confirmed penicilliosis will be recruited, randomly allocated to eitheritraconazole or amphotericin B treatment, monitored daily in-hospital for 2 weeks, and at monthly intervalsfor a total of 6 months. Primary outcome is mortality at 2 weeks. Secondary outcomes include 6-monthsurvival, clinical response, relapse, drug tolerability, and economic costs. Correlates of interests includeadmission prognostic factors, time-to-culture-sterilization, fungicidal activities, pharmacokinetic parameters,and serologic titres. These results will be available within five years and will either change or support currenttreatment guidelines for penicilliosis.

Amount: £305,683
Funder: The Wellcome Trust
Recipient: University of Oxford

From Sail to Steam: Health, Medicine and the Victorian Navy 11 Nov 2010

The programme seeks to determine the degree to which the Navy affected the development of medicine in Britain and how effectively the Navy was able to deal with the medical challenges posed by the transition from sail to steam and its new imperial role. Firstly, this study will place the Navy at the centre of debates over disease causation and public health, domestically and internationally, as the Navy was the focus of several diplomatic incidents involving the spread of infection. The research programme will also explore the Navy's formative influence upon the development of state health care and on disciplines such as epidemiology. Secondly, the research programme will place health and medical considerations at the centre of naval historiography, showing that naval health became an important political subject from the 1840s and that the operational difficulties posed by disease and medical care had much broader ramifictions. In order to understand how successfully the Navy coped with such problems, the project will examine the status of naval surgeons and their ability to effect reform on naval vessels. These goals will be realized in the form of several scholary monographs and articles and through engagement with the public and serving naval officers.

Amount: £716,130
Funder: The Wellcome Trust
Recipient: University of Oxford

Spatial and temporal patterns of gene flow in Plasmodium falciparum can informprophylaxis administration strategy and vaccine design 31 Aug 2011

Spatial and temporal patterns of gene flow in Plasmodium falciparum and other infectious diseases

Amount: £156,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural investigation of the Hepatitis C Virus capsid assembly 31 Aug 2011

Hepatitis C Virus infection can cause chronic liver pathologies such as cirrhosis and hepatocellular carcinoma. With at least 130 million people infected world wide, the drive to understand and treat this virus is pressing. The core protein is responsible for the formation of the capsid that protects the viral genome. However very little is known about the structural information of the capsid. This project aims to elucidate the three-dimensional structure of the capsid by electron microscopy and X-ray crystallography. Further biophysical characterisation of the capsid will help to further our understanding of the molecular details of this medically relevant virus. The project then aims to discover and characterise novel inhibitors of assembly as a potential antiviral therapy.

Amount: £156,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding the mechanism of cohesion establishment 31 Aug 2011

The cohesin ring topologically entraps sister chromatids to ensure timely and error-free chromosome segregation during cell division. In interphase, cohesin is continually loaded onto and removed from the DNA by kollerin and releasin complexes, respectively. Acetylation of the ring is crucial for cohesion establishment this modification is believed to overpower the antiestablishment activity of releasin. In many systems outside of yeast, another essential protein sororin is also required for releasin neutralisation. One of the minor aims of this project is to conduct a small-scale screen to determine whether or not sororin exists in Saccharomyces cerevisiae. The primary goal of this project is to investigate the anti-establishment activity of releasin. One of the key aims is to determine whether releasin has the ability to physicallyremove cohesin from both DNA strands. The bulk of this project will involve reconstituting releasin activity in vitro by building on an existing physical assay for cohesion. Ultimately, this project aims to establish the minimal requirements for the anti-establishment activity of releasin.

Amount: £156,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Infection, Immunology and Translational Medicine - 'Establishment of a transgenic zebrafish model to study the innate immune response to melanoma' 12 Jul 2011

Although immune mechanisms, such as cytokines produced by immune cells in response to the tumour environment, may provide protection against cancer by elimination of transformed cells, they may also aid tumour development by immunosuppressive mechanisms. Epigenetic mechanisms that alter chromatin landscape, enabling the unwrapping of transcriptional programs play important roles in all cellular processes including immune response mechanisms and carcinogenesis. It remains difficult to assess the overall effect of innate immunity during early tumourigenesis since direct in vivo models for evaluating the effects ofthese phenomena on initial tumour growth are missing. We propose to develop a melanoma model in zebrafish to study the initial host immune response to melanoma with particular focus on epigenetic changes. Key Goals 3.1 Establish a zebrafish model system to study the innate immune response to melanoma. 3.2 Characterise the interaction of neutrophils and macrophages with oncogenicmelanocytes as compared to normal melanocytes in vivo. 3.3 Carry out a genome-wide analysis of macrophages and neutrophils' response to melanoma compared to control melanocytes. i. Identify differentially expressed genes by comparing transcriptomes of innate immune cells ii. Identify changes at the epigenomic level in innate immune cells that may be resulting in differential cytokine expression 3.4 Investigate findings in melanoma patients.

Amount: £156,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Infection, Immunology and Translational Medicine - 'Investigating the mechanism of non-catalytic tyrosine phosphorylated receptor triggering' 12 Jul 2011

The central goal of this project is to investigate the mechanism of non-catalytic tyrosine phosphorylated receptor (NTR) triggering. These receptors share a number of features. For example, they contain, or associate with adaptor molecules that contain, tyrosine residues that are phosphorylated by extrinsic kinases, and have comparatively small extracellular domains which bind surface-associated ligands. Our hypothesis is that the kinetic-segregation model, initially proposed to explain T cell receptor triggering, applies to all othermembers of the NTR family. A number of recent reports including work with natural killer cell receptors have provided evidence to support this notion. This project aims to develop and validate a number of generic techniques for systemically investigating the mechanism of NTR triggering and testing the KS model. Imaging, biochemical studies and functional assays will all be utilisedto aid in this. In parallel, a more in-depth analysis of a small subset of NTRs from various subgroups of the family, including leukocyte-associated immunoglobulin-like receptor 1 will be conducted. These experiments will complement the artificial system developed for large-scale systemic investigations of numerous NTRs, by utilising more physiological settings, including the use of natural ligands and primary cells that normally express the NTR.

Amount: £156,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Action costs and competition costs in reward-guided decision making 12 Jul 2011

I propose to use functional magnetic resonance imaging in combination with computational modelling to investigate questions of learning and decision making. The proposed project aims to understand how the brain processes action-related and social information to minimise decision costs. More specifically, it is intended to examine whether there are brain mechanisms underlying learning and decision making that do not relate specific occurrences of stimuli to specific occurrences of outcomes, as commonly thought, but which instead are based on the rate of reward received over time and the rate of action that is emitted. In some other contexts, where more than one individual is present then it may be the case that an agent will alsocompare their action-reward rates with those that appear to be experienced by other competing agents. From a foraging perspective both sets of information, although seemingly disparate in nature, can be understood as key parameters determining decision costs. In investigating the brain mechanisms underlying the inclusion of these costs in decision making, the research project particularly aims to understand the roles of various frontal cortical regions, especially the cingulate cortex

Amount: £155,726
Funder: The Wellcome Trust
Recipient: University of Oxford

Extension to A record- funds for sequencing: Measuring the impact of naturally acquired immunity on the expression of Plasmodium falciparum variant surface antigens. 31 Aug 2011

Plasmodium falciparum infected erythrocytes express on their surface, members of a diverse family of parasite molecules called PfEMP1 that are encoded by a family of 60 var genes. These molecules interact with the surface of host cells and mediate parasite sequestration in tissues including the brain, an important step in the pathogenesis of cerebral malaria. Although naturally acquired antibodies to PfEMP1 provide specific protection against the molecular variants that they recognise, PfEMP1 ar e often considered too diverse to be vaccine candidates. However, we and others have shown that parasites infecting children with severe malaria tend to express serotypes that are more broadly recognised suggesting they may be antigenically restricted. Studies of a laboratory isolate suggest that the most broadly recognised PfEMP1 types are encoded by a genetically distinct subset of groupA var genes. By sequencing short var sequence tags expressed in parasites from Kenya, we have shown that expression of sequences with groupA-like features are associated with younger children and that a smaller subset of these sequences are associated with severe malaria. We propose to identify new targets of malaria intervention by characterizing these specific subsets of PfEMP1 that are associated with infections of children with low natural immunity.

Amount: £34,024
Funder: The Wellcome Trust
Recipient: University of Oxford

Developing treatments for mitochondrial DNA diseases. 09 Mar 2011

We will test whether mitophagy (a catabolic process involving recycling of damaged mitochondria) is important in mitochondrial disease. We aim to overcome the technical difficulties of studying mitophagy using: (1) ImageStream (which combines flow cytometry and fluorescence microscopy in a single platform) to investigate patient-derived cell lines. We will explore how mitophagy is affected in cells with defects of mtDNA maintenance, from patients and from the POLG1 deficient Mutator mouse. We will explore whether mtDNA mutant populations can be manipulated by modulating mitophagy, for instance by amino acid starvation and exposure to certain drugs including rapamicin and chloroquine. (2) a mouse model in which mitophagy may be readily detected by florescence microscopy. This involves crossing two existing transgenic strains in order to breed mice in which mitochondria and lysosomes both constitutively express fluorescent markers. Mitophagosomes would thus be detectab le by co-localisation of these signals, providing a marker for response to therapies. This mouse will be crossed with an existing model (the Deletor mouse) to determine how candidate treatments (including ketogenic diet) affect mitophagy. These approaches will be extremely useful tools for investigating multiple mitophagy-related pathologies and mouse models of mtDNA diseases and ageing.

Amount: £251,826
Funder: The Wellcome Trust
Recipient: University of Oxford

Mechanisms of associative action learning. 17 Jan 2011

A major challenge in neurobiology is to explain how experiences can alter a brain to incorporate new information about (1) relationships between stimuli and (2) which actions are consequential. Both kinds of associative learning have been extensively studied, but much less is known about the latter. The fly Drosophila can be trained to form associations between a painful heat pulse and a specific motor program. The lack of external stimuli suggests that this associative process employs informati on about the animal s actions. This information is proposed to be carried by (1) the corollary discharge and reafferent signals that arise from motor commands (2) biochemical signaling pathways that mediate neural plasticity and (3) action representation neurons whose activity is modified by conditioning. I will search for these systems with neurogenetic loss-of-function experiments.

Amount: £132,390
Funder: The Wellcome Trust
Recipient: University of Oxford

Genetic basis of craniofacial malformations. 14 Oct 2010

1. Prospective ascertainment of patients requiring craniofacial surgery at the four participating centres. We will aim to recruit a minimum of 150 patients (with parents) annually. 2. Identification of new monogenic causes of craniofacial malformation within this cohort using massively parallel sequencing. We will use 16 lanes of Illumina-based sequencing of captured whole exomes in patients or parents chosen because of a combination of positive family history, evidence of progressive feature s, distinctive phenotype or suspected de novo mutation. We will use bioinformatic analysis, including knowledge of gene expression and protein interaction networks affected by known craniofacial mutations, to prioritise genes for further sequencing. 3. We will assess the genetic impact of candidate mutations by DNA sequencing and analysis of exon copy number in the larger cohort, to establish the presence of mutations in the wider sample resource, and determine mutation spectrum, prevalence an d genotype-phenotype correlation. 4. We will undertake studies on the expression of identified genes in murine cranial sutures or other craniofacial structures, and relevant functional assays. 5. As a long-term goal we wish to acquire surgical and developmental outcome data linked to genotype.

Amount: £489,226
Funder: The Wellcome Trust
Recipient: University of Oxford

Neuropharmacological modulation of functional brain imaging signals in awake and anaesthetized rats. 07 Oct 2010

Despite much research, there are still significant gaps in our understanding of what neuroimaging signals tell us about neuronal activity. Firstly, almost all previous research addressed to this question has utilized anaesthetized animals despite established effects of anaesthesia on neuronal, haemodynamic and neurovascular function. Secondly, little work has investigated the neurophysiological basis of neuroimaging signals in important subcortical structures. Thirdly, little is known about how experimental, disease-related, or therapeutic alterations in the function of major neurotransmitter systems such as the serotonin system affects the relationship between neuronal and fMRI responses. This project is centred on an experimental design that will provide data to address each of these gaps in current knowledge. In both awake and anaesthetized rats, we propose to determine the relationships between the neuronal, metabolic and fMRI responses to activation of two subcortical structur es of major clinical and scientific importance: the amygdala and the striatum. We will then determine the effects of alterations in serotonergic neurotransmission upon these relationships. To achieve this, we will combine in-vivo measurements of neuronal activity (electrophysiology), tissue oxygen and glucose (voltametry) and fMRI signals (both BOLD and CBV imaging) with pharmacological and electrical stimulation methods in (trained) awake and anaesthetized rats.

Amount: £256,289
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural role of BET bromodomains in transcription. 22 Jun 2011

This project aims to address the structural role of BET bromodomains in transcription initiation and the implications of disrupting this role in disease, when for example BETs are found fused to the NUT (nuclear protein in testis) protein or when they are associated to viral oncoproteins. To do so I will employ high throughput structural biology techniques to study BET bromodomains, aiming to establish an interaction map with their substrates, understand the molecular details of substrate intera ctions, explain synergy between multiple BET dromodomain modules, explore the molecular and structural basis of their interactions with the positive transcription elongation factor b (P-TEFb), structurally characterize their oncogenic fusions to NUT and probe the molecular and structural basis of their interactions with viral oncoproteins.

Amount: £1,036,653
Funder: The Wellcome Trust
Recipient: University of Oxford

Finding Solutions to Moral Dilemmas in Ethically Charged Contexts: the case of Paediatric HIV/AIDS research in Developing Country settings. 17 Mar 2011

The proposed study aims to critically examine the normative implications of solutions arrived at by field-level research actors in the context of paediatric HIV research. This aim will be addressed throughout this study in two complementary ways: 1. A descriptive component (of both the dilemmas experienced and of the solutions devised); 2. A normative component (critically examining and analysing the moral features of the solutions identified by research-actors and their potential applicab ility to other settings). This study will examine the PENTA BREATHER randomised control trial, which aims to assess whether intentionally interrupting the antiretroviral therapies (ART) received by HIV-positive, 8-21 year olds, has a significant impact on their viral load. The solutions devised by field-level research actors involved in this trial will be examined using ethnographic and qualitative techniques alongside philosophically informed case-based approaches. This research will take place at three sites: the UK, Uganda and Brazil. These locations have been chosen to represent a variety of contexts with differing health systems, socio-economic conditions and mortality and morbidity rates.

Amount: £186,144
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural and functional connectivity and association to cognitive performance in memory disorders. 20 Jun 2011

Background: Memory disorders are a significant source of morbidity. They are common with over 800,000 patients with dementia in the UK, a number expected to double over the next 20 years. Project aims: (i)Map structural and functional alterations to cognitive performance in diagnostic groups, considering the importance of structural and functional connectivity and integral structures (eg hippocampus) (ii) Explore the role of structural and functional connectivity in the neurobiology of me mory deficits. (iii) Develop novel image analysis methods that may aid diagnosis and understanding. Study Design and Methodology: Three groups will be compared using an advanced multi-modal imaging MRI protocol: a. Autoimmune limbic encephalitis (n=20), b. age/sex matched patients with early Alzheimer's disease (n=20), c. age/sex matched healthy controls (n=20). MRI brain protocol will include structural imaging, DTI, fMRI and Perfusion. Magnetoencephalography (MEG) and 7 Tesla MRI scan wi ll be performed on a subgroup. MRI analysis includes voxel wise diffusion indices and resting networks. Neuropsychological testing protocol will be performed. Correlates of MRI findings with neuropsychological markers will be sought. Opportunities: These studies will investigate the neurobiology of memory in limbic encephalitis and Alzheimer's disease. This may help in detection and treatment of these diseases and related memory disorders.

Amount: £203,390
Funder: The Wellcome Trust
Recipient: University of Oxford