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University of Oxford

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Medical and Literary Language in the Late Fourteenth Century. 19 Oct 2010

This research has two goals: to demonstrate how literary texts used medical discourse as a rich source of imagery and narrative techniques in the late fourteenth-century and to explore how and why medical writers used literary devices to make sense of illness. I am interested generally in the question of how English literature invented itself by channelling other registers e.g. historical writing and practical discourses. Exploring seemingly generically diverse texts side by side will, I h ope, demonstrate how these kinds of writing acted upon each other as English literature emerged in force. I will also explore how medical writers especially Arderne used literary devices. Why do writers seek to understand illness through story-telling and through metaphor? I recently discovered that Arderne treated Thomas Usk and this has led me to think more about links between doctors and writers (Arderne advises doctors to be like clerks ) and between their texts (Arderne may have us ed the Gawain-poet s illuminator; the countess of Devon bequeathed romances and medical tracts together). Key texts include Arderne s writings, the Livre de seyntz medicine, penitential manuals, and poetry by Chaucer and the Gawain-poet; both genre theory and disability studies are important frameworks for this research.

Amount: £13,191
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

Role of non-muscle myosin II in Caenorhabditis elegans stem-like seam cell asymmetric division 31 Aug 2011

Caenorhabditis elegans (C. elegans) stem cell-like seam cells undergo both symmetric and asymmetric divisions during larval development, thus providing a powerful system to study cell proliferation versus differentiation. The aim of my proposed research is to study how C. elegans seam cell asymmetric divisions are regulated. We have obtained preliminary data in which nmy- 2 was knocked down by RNAi, suggesting that a non-muscle myosin II-dependent mechanism may be responsible for ensuring proper seam cell asymmetric divisions. I will focus on the role of nmy-2 in this process, mainly by high-resolution microscopy and video lineage analyses of cell divisions in both RNAi-treated worms and mutant worms. Our early evidencesuggests that nmy-2 plays an important role in regulating seam cell asymmetric divisions.

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

Molecular mechanisms of Repulsive Guidance Molecule (RGM) action 31 Aug 2011

Repulsive Guidance molecules (RGMs), a family of membrane-anchored glycoproteins, are involved in two key signalling pathways: the Neogenin (NEO1) [1] and bone morphogenetic protein (BMP) [2] pathways. RGMs control and fine-tune a wide range of functions from neural development [3] to leukocyte migration [4], and are implicated in several severe diseases, for example juvenile hemochromatosis [5,6] and cancer [7]. The aim of this research project is to fully characterise the actions of RGMs at the membrane interface with both of these pathways. This will involve biophysical and cell-based measurements to build on a crystal structure of RGM bound to BMP (obtained in my first rotation project) to understand how RGMacts as an activator in this pathway. It will also involve crystallisation of complexes involving proteins from both pathways to study how the two pathways are connected. I will also work towards crystallising the full-length type I membrane protein BMP-receptors to gain insight into how the signal is transmitted across the membrane. This will be supported by functional studies using fluorescence techniques, biophysical and cellular analyses.

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-'Towards the development of auniversal influenza vaccine:Investigation of heterosubtypic humoral and cellular immune responses to influenza induced by vaccincation with viral 12 Jul 2011

Seasonal influenza epidemics and pandemics are associated with a non-trivial mortality, morbidity and carry a heavy socioeconomic burden. Vaccination is still the primary strategy for the prevention and control of influenza despite the limitations of currently licensed vaccines and their requirement of periodic reformulation and annual revaccination of at-risk individuals. A first generation T-cell inducing influenza vaccine developed at the Jenner Institute has demonstrated partial efficacy in a human trial. However, there is further workto be done in terms of targeting other conserved antigenic sites that can efficaciously provide heterosubtypic B cell immunity between multiple strains of influenza. We hypothesise that by targeting both arms of the adaptive immune system through rational vaccine design this could provide the highest level of protection against seasonal and pandemic flu. I will assess this by (i) designing new viral vector vaccines that targetcellular and humoral immunity, (ii) testing appropriate regimens in preclinical studies, (iii) measuring induced immunity to influenza antigens and (iv) delineating the mechanisms of B cell memory induction. As we are interested in assessing the use of these candidate vaccines in combination with or as a booster to seasonal influenza vaccination I will investigate a best in class' regimen including our novel vaccine.

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

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

The role of CNTNAP2 in the Cerebellum 12 Jul 2011

The cerebellum is increasingly implicated in higher cognitive function and cerebellar dysfunction has been linked to several diseases. Recently, there has been accumulating evidence for the involvement of the cerebellum in autism. Cntnap2 -/- mice have been described as a model of autism. In this project, I aim to investigate Cntnap2 function in the cerebellum. I will analyse its cerebellar expression patterns during development and aim to elucidate its role at the synapse of parallel fibres. I will test whether Cntnap2 -/- mice also display a cerebellar behavioural phenotype in addition to the previously described autism-like phenotype. Finally, I aim to rescue Cntnap2 expression in cerebellar granule cells by crossing the Cntnap2 knockout mice with Math1-Cntnap2 transgenic mice and asses motor and autism-like behaviour

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

CpG island binding proteins: elucidating the function of the histone demethylase KDM2 and the leukemic histone methyltransferase MLL in the zebrafish. 21 Feb 2011

The aim of this research proposal is to investigate how the ZF-CxxC domain containing KDM2 and MLL proteins contribute to CpG island function, chromatin modification, and development in the model organism the zebrafish (Dania rerio). 1) To identify zebrafish orthologues of ZF-CxxC KDM2 and MLL proteins and examine their biochemical properties. 2) To perturb the expression of KDM2 and MLL and to analyse the phenotypic consequence during development. 3) To examine mechanistically the domain function of KDM2 and MLL by targeted rescue experiments.

Amount: £35,692
Funder: The Wellcome Trust
Recipient: University of Oxford

The role of haematopoietic lineage cells in the TMEV model of multiple sclerosis. 31 Aug 2011

This proposal addresses the role of haematopoietic lineage cells (HCs) in disease persistence and spread in a viral model of multiple sclerosis (MS). We hope to determine the cell type and route of entry of HCs into the central nervous system (CNS) using a combination of immunohistochemistry, molecular biology and 2-photon slice imaging. Using molecular biology techniques we will investigate the mechanistic hypothesis that galectin-3 is necessary for Theiler's murine encephalitis virus (TMEV) induced HC recruitment and migration.

Amount: £13,694
Funder: The Wellcome Trust
Recipient: University of Oxford

Medicine and Deaf Education in Japan: the Meiji Period,1868-1912, and Today 08 Jun 2011

This proposed research has two key goals: to understand how the 'Westernization' of medicine and education during the Meiji Period affected deaf Japanese and to grasp the extent to which the current educational situation reflects ideologies from this historical turning point. The first step is to conduct in-depth historical research into transformations in both the medical and educational systems during the Meiji Period. Extensive medical and educational archival research and a critical review of other primary and secondary sources would be conducted. As Japan has a rich oral culture, it could prove extremely beneficial to interview descendants of deaf Japanese who were educated during the Meiji Period. In order to evaluate contemporary deaf education, participant observation at a deaf school would be undertaken. This would involve observing deaf students in the classroom setting as well as conducting in-depth interviews with deaf students and their educators. In addition, a critical review of the recent literature on deaf education would be done. The final step would be to compare, contrast, and critically discuss Meiji Period attitudes toward the deaf and the contemporary deaf student's experience to determine the extent to which deaf schools today reflect the negotiation of Western and Japanese ideologies.

Amount: £96,334
Funder: The Wellcome Trust
Recipient: University of Oxford

Wellcome Trust Clinical PhD Programme at the University of Oxford: 'The role of the G-protein subunit Galpha11, in the regulation of calcium homeostasis. 31 Aug 2011

G-protein coupled receptors (GPCRs) play a central role in facilitating cellular responses to diverse extracellular stimuli such as ions, metabolites and hormones. Moreover, GPCR mutations result in diseases that include tumour development and endocrine dysregulation. One such GPCR is the calcium-sensing receptor (CaSR), mutations of which cause familial benign hypocalciuric hypercalcaemia (FBHH) and parathyroid tumours. However, only approximately 65%of FBHH patients harbour CaSR mutations. GPCRs signal through association withheterotrimeric G-proteins that consist of alpha, beta and gamma subunits, and the CaSR specifically signals via Galphaq/11, Galphai and Galpha12/13. Professor Thakker's group therefore postulated that FBHH patients without CaSRmutations may have mutations in these downstream heterotrimeric G-proteins andidentified Galpha11 mutations in FBHH patients. My key goal is to determine the role of Galpha11 in the CaSR signalling pathway and in calcium homeostasisby: 1) Characterising the in vitro effects, by transient transfection assays, of the Galpha11 mutations in the CaSR signalling pathway. 2) Determining the in vivo role of Galpha11 and its mutants by investigating wild-type and established N-ethyl-N-nitrosurea (ENU) mutant Galpha11 mice. 3) Undertaking pharmacological studies using Galpha11 inhibitors and targeted peptides to determine their in vitro and in vivo modulatory effects.

Amount: £262,814
Funder: The Wellcome Trust
Recipient: University of Oxford

Adaptive coding and plasticity in the auditory system. 07 Oct 2010

This research aims to improve our understanding of the neural basis for auditory perception by investigating how experience shapes the way in which information is represented in the mature brain. We plan to use electrophysiological recording and imaging techniques in ferrets to determine how the neural processing of sounds at higher levels of the auditory pathway adapts over different time scales, both according to the context in which those sounds occur and as a result of perceptual learning. W e shall explore the perceptual consequences of those changes by combining electrophysiological and behavioural measurements in the same animals. Psychophysical tests in humans will also be used to assess the generality of these findings and to guide subsequent animal studies. By employing methods for silencing specific neural pathways, we hope to identify the neural circuits responsible for the dynamic processing of auditory information, while recordings from cortical and subcortical areas will reveal how neural coding strategies change as a result of learning and experience. We shall focus primarily on the adaptive coding and plasticity of auditory spatial information, both under normal hearing conditions and after reversibly altering the localization cues available or following the re-introduction of auditory function by bilateral cochlear implantation.

Amount: £2,715,428
Funder: The Wellcome Trust
Recipient: University of Oxford

Upregulation of early inflammation to accelerate repair of fragility fractures. 20 Jun 2011

Fragility fractures as a result of osteoporosis are an enormous public health burden and are associated with excessive patient morbidity and mortality. The poor bone quality results in slower healing and predisposes to failure of orthopaedic implants used to stabilise the fractures. Currently there is currently no approved therapy for accelerating healing of fragility fractures. Thus, strategies to achieve this goal represent a major unmet medical need. We have previously reported that targe ted augmentation of the early inflammatory response at the fracture site can enhance fracture repair through the recruitment and differentiation of resident mesenchymal stromal cells in our murine model. This proposal aims to first, determine whether these findings also apply to osteoporotic bone, and second, dissect the pathways that lead to inflammatory cytokine production to determine the most effective point of intervention. The overall aim is to develop a clinically translatable strategy for accelerating the healing of fragility fractures by using a combination of primary human tissues and murine models.

Amount: £249,591
Funder: The Wellcome Trust
Recipient: University of Oxford

Regulation of monocyte function by iNKT cells in normal subjects and sarcoidosis. 25 Nov 2010

Invariant NKT cells are a unique subset of immuneregulatory cells, able to prevent expansion of antigen-specific T cells. I hypothesise that iNKT cells influence the proliferation and function of monocytes, and that defects in this control pathway in conditions like sarcoidosis (where there is a lack of iNKT cells), results in abnormally activated pro-inflammatory macrophages and granulomagenesis. The effects of iNKT cells on monocytes in normal individuals will be studied by examining the e ffect of iNKT clones on monocyte function. Monocytes will be co-cultured with iNKT cells or control, after which I will examine the impact of iNKT cells on monocytic (i) phagocytic ability (ii) phenotypic changes (iii) ability to stimulate T cell proliferation and (iv) global gene expression post LPS stimulation I will also study monocyte phenotype and function in sarcoidosis patients compared to controls (healthy and other respiratory disease) by examining (i) IL-10 and TNF-alpha secretion ( ii) markers of monocyte differentiation (iii) phagocytosis capacity and (iv) differentiation after LPS stimulation. The work will contribute to research in regulation of monocyte function, improve understanding of disease mechanisms in sarcoidosis, and provide a platform for potential immune cellular therapeutic intervention.

Amount: £265,723
Funder: The Wellcome Trust
Recipient: University of Oxford

Bridging the gap from type 2 diabetes genetics to functional mechanisms of disease. 13 Apr 2011

The overall objective of the Fellowship is to elucidate the functional mechanisms whereby genetic variants shown to influence Type 2 diabetes (T2D) predisposition exert their effects at the molecular, cellular and whole-body level. Initially, I will build on my existing research activity to explore the functional consequences of variants in three established T2D-susceptibility genes. I will: (a) determine the molecular mechanisms by which glucokinase promoter variants influence fasting gluco se levels and T2D-risk; (b) continue efforts to enumerate the full allelic spectrum of variants in the glucokinase regulatory protein gene, and to relate these variants to cellular, kinetic and clinical phenotypes; and (c) analyse human islets and rodent models to establish the mechanisms whereby variation in the adenylate cyclase 5 gene influences glucose homeostasis. In parallel, I will initiate functional characterisation of selected low frequency variants of moderate-to-large effect emer ging from ongoing high-throughput resequencing efforts in T2D. I will focus on variants which appear to mediate their T2D-risk through abrogation of islet function, using a combination of genetics, cellular and molecular biology and human physiology to reveal the mechanisms responsible. This work is expected to provide powerful insights into the pathophysiology of T2D that will support translational advances in disease management.

Amount: £1,497,580
Funder: The Wellcome Trust
Recipient: University of Oxford

Epistasis and the genetics of disease resistance 23 May 2011

I have shown that two epistatic interactions (a cancellation of malaria protection when alpha thalassaemia and sickle cell are coinherited, and an alleviation of blood disorder when alpha and beta thalassaeamia are coinherited) could explain aspects of the distribution of the malaria protective haemoglobinopathies: particularly the rarity of sickle cell in the Mediterranean region (Penman et al, 2010). The goals of the first part of this proposal are to (i) use mathematical models to determine w hether epistasis could account for the east/West divide between sickle cell and HbE; (ii) analyse a detailed population genetic dataset from Kenya to look for new epistatic interactions between malaria protective genes, and (iii) conduct in vitro studies to determine whether erythrocytes carrying both alpha and beta thalassaemia offer malaria protection. Two crucial sets of human immune system genes: the HLAs and the KIRs display striking genomic organisation. For the second part of this p roposal, my goal is to investigate whether epistatic interactions could help maintain HLA and KIR haplotypes. I will build mathematical models that capture the interplay between HLA loci, KIR loci and pathogen selection, and test the models predictions against HLA and KIR sequence data in online databases.

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

'The Global Health Bioethics Network: a programme to carry out ethics research and build ethics capacity across the Wellcome Trust's Major Overseas Programmes.' 12 Apr 2011

Enormous global inequalities exist in health measures such as mortality, quality of life and disease despite increasing levels of overall wealth. In recent years, partly because of initiatives like the Wellcome Trust s Major Overseas Programmes (MOPs), there has been an unprecedented increase in the amount of research carried out on global health. Global health research, often bringing together multiple partners from sites in developing and developed countries, presents a range of important ethi cal and social issues not previously found in combination. These include issues relating to the sharing of data and biological samples between developing and developed countries, and to the question of what is to count as valid consent in the context of research occurring in multiple developing country settings. Identifying and addressing these important issues is essential for successful and appropriate science and for the achievement of the goals set out in the Wellcome Trust s Strategic Plan. The MOPs do not currently have sufficient capacity in ethics and community engagement to effectively engage with these important problems. Against this background, the aim of this proposal is to build ethics expertise and capacity across the MOPs by combining world-class research with a well-managed programme of networked, locally-driven capacity-building activities.

Amount: £1,115,284
Funder: The Wellcome Trust
Recipient: University of Oxford

Bio-Ethics Bites. 14 Dec 2010

Neuroscience is challenging our traditional understanding of consciousness, responsibility, morality and well-being, a challenge that also raises new problems for ethics and clinical practice concerning addiction and criminal responsibility, the treatment of vegetative patients, medical decision-making and the enhancement of normal human capacities. The new discipline of neuroethics addresses these urgent issues. Our goals are to: Establish a Wellcome Centre for Neuroethics at Oxford University, bringing together interdisciplinary expertise from ethics, philosophy of mind, law, psychiatry and neurosciences to contribute to neuroethical research, focussing on four areas: 1. Cognitive and affective enhancement 2.Borderline consciousness and severe neurological impairment 3. Free will, responsibility & addiction 4. Neuroscience of morality and decision-making Conduct applied research which aims to use neuroethics and practical ethics in general to address: (1) advances in neuroscientific technology; (2) ethical issues arising from research and clinical practice in neuroscience. Facilitate neuroethical research internationally by creating a metacentre which brings together leading international researchers from relevant disciplines. Apply the results of our research to specific problems in biomedical policy, law and practice and to disseminate them to influence policy and promote public debate.

Amount: £10,000
Funder: The Wellcome Trust
Recipient: University of Oxford