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Recipients:
University of Oxford

Results

An Empirical Study of Children and Adolescents' Perspectives on Testing Minors for their Genetic Predisposition to Psychiatric Disorders 10 May 2016

Predictive genetic testing for psychiatric disorders could help prevent or delay the development of debilitating conditions. However, the complex inheritance, incomplete penetrance, and variable expression in the genes underlying mental disorders make such testing a relatively poor predictive instrument. Empirical studies investigated the socio-ethical impacts of such testing from the perspectives of adult patients, family members, psychiatrists, and geneticists, who highlighted the risk of promoting a deterministic stance on psychiatric conditions, of discrimination against and stigma of the individuals tested, and the potential negative effects on family relationships. However, no systematic study has investigated minors’ perspectives. This is an important gap in the debate, as minors are likely to be the main target of psychiatric genetic testing. Therefore, the aim of my research is to investigate children and adolescents’ perspectives on testing minors for their genetic predisposition to psychiatric disorders. My research will assess whether their concerns confirm those expressed in the academic literature and it will provide a more inclusive account of the public’s opinions, thereby promoting an ethically robust application of scientific discoveries in this field. I will conduct a systematic review of the ethics literature on psychiatric genetic testing in minors and a systematic qualitative interview study.

Amount: £93,065
Funder: The Wellcome Trust
Recipient: University of Oxford

The Role of the Adaptor Protein-2 Sigma Subunit (AP2σ) in Calcium Homeostasis 30 Sep 2016

G-protein coupled receptors (GPCRs) facilitate cellular responses to extracellular stimuli, and GPCR mutations result in many diseases, including endocrine disorders. Mutations of the calcium-sensing receptor (CaSR), a pivotal GPCR in calcium homeostasis, resulting in loss-of-function or gain-of-function cause familial hypocalciuric hypercalcaemia type-1 (FHH1) and autosomal dominant hypocalcaemia type-1 (ADH1), respectively. FHH and ADH are genetically heterogeneous, and loss-of-function or gain-of-function mutations of the G-protein-alpha11 utilised by CaSR, cause FHH2 and ADH2, respectively; while loss-of-function mutations of adaptor protein-2 sigma subunit (AP2sigma), which is critical for clathrin-mediated endocytosis, cause FHH3. To date, the reported AP2sigma mutations, which cause only FHH3 but not ADH, all affect residue Arg15 and impair CaSR signalling and trafficking. However, the Thakker group have recently identified seven other AP2sigma variants (Arg3His, Ala44Thr, Phe52Tyr, Arg61His, Thr112Met, Met117Ile, Glu120Gly), and my goal is to determine the roles of these AP2sigma variants in calcium homeostasis by: 1) Characterising their structural-functional relationships by in vitro studies that assess effects on three-dimensional models and on CaSR signalling and trafficking pathways. 2) Determining in vivo phenotypes of AP2sigma mutations by generating knock-in mouse models, using CRISPR-Cas. 3) Assessing pharmacological effects of drugs, e.g. velcalcetide, using above AP2sigma in vitro and in vivo models.

Amount: £348,449
Funder: The Wellcome Trust
Recipient: University of Oxford

Activity-dependent plasticity of long-range sensorimotor connectivity. 02 Dec 2015

This proposal will consider when and how activity-dependent plasticity of long-range brain connections occurs, and will assess its behavioural significance. The programme will include work ranging from cellular level studies of the underlying biology in rodents, and basic science studies in human volunteers, through to proof of principle trials in clinical populations. The proposal includes the following work packages: 1. Manipulating activity These projects use neurofeedback to alter hu man brain activity in order to test whether modulating activity in specific sensorimotor circuits can produce rapid and bidirectional changes in brain connections and change behaviour. 2. Manipulating behaviour. This programme will test whether reduced limb use results in altered functional and structural connectivity. 3. Underlying biology Studies in transgenic rodents will assess whether myelin change contributes to plasticity of brain connections. Secondary questions concern the role of sleep in observed changes in brain connections and behaviour. 4. Boosting plasticity of brain connections for rehabilitation In our final work package, we will apply principles established from the basic science programme described above to stroke rehabilitation. First, we will assess whether neurofeedback can be used to rebalance motor-related activity after stroke. Second, we will test whether improving sleep quality after stroke can affect rehabilitation outcomes, due to the importa nce of sleep for consolidation of motor learning.

Amount: £2,481,628
Funder: The Wellcome Trust
Recipient: University of Oxford

Public Engagement for the Thailand Major Overseas Programme 2015 - 2020 30 Apr 2016

The mission of the Wellcome Trust Thailand Major Overseas Programme is to carry out targetedclinical and public health investigations, using the best science, to provide appropriate andaffordable interventions which produce measurable improvements in the health of resource-poorpopulations in the tropics. Over the past 35 years the Programme has built substantial clinicaland laboratory research capabilities, deployed across a well-integrated network of strategicallyplaced permanent study sites and research units in seven countries across Asia and Africa. Wewill use this expertise and research capacity to tackle the epidemiology, diagnosis,pathophysiology, treatment, prevention, and, in the case of malaria, elimination of thoseunderstudied infectious and nutritional diseases that cause significant morbidity and mortality inthe populous rural tropics. In doing so we will strengthen local research capacity, a majorobjective of the programme, and build lasting south-south research collaborations with ourpartners across the developing world. We will inform health policy, change clinical practice, andmake a global impact on mortality from tropical infectious disease.

Amount: £618,799
Funder: The Wellcome Trust
Recipient: University of Oxford

Clinical Genomic Medicine and the Need for a Public Health Ethics Account 13 Jan 2016

The implementation and practice of clinical genomic medicine increasingly employs a population perspective in the utilisation of data and the integration of genomics within healthcare systems. However, the contemporary accounts of ethics and genomics tend to lag behind, focussing primarily on the best interests of individuals and their families. These ethical accounts are unsuited to addressing the new ethical problems resulting from the population approach in clinical genomic medicine e.g. the use of population level data sets to interpret variants of unknown significance. Might an account built upon public health ethics, which tends to emphasise the balance between protecting and promoting the health of populations, whilst avoiding individual harm, be more suited to the assessment of clinical genomic practice? This research will explore whether public health ethics can offer a more fitting and practical account for the ethics of clinical genomic medicine. The key research goals include combining empirical and normative analysis of public health ethical values for application in clinical genomic medicine, the formulation and dissemination of practical guidance and useful recommendations for application in clinical genomic medicine policy and practice. The methodology employed will involve conceptual ethical analysis and qualitative interviews with key stakeholder groups in the UK.

Amount: £289,647
Funder: The Wellcome Trust
Recipient: University of Oxford

Reconstructing Nicholas Crouch: conserving a seventeenth-century medical reader 25 Nov 2015

Balliol College proposes an exciting project to open up a truly inter-disciplinary collection, one where printed books become manuscripts, and the Sciences and Humanities meet: the library of Nicholas Crouch (ca.1618-1690), Oxford medical academic and practitioner. Balliol College has a strong commitment to its historic collections, including bespoke facilities and dedicated staff to support teaching, research and public outreach. We look to the Wellcome Trust to help us extend our finite resources to employ specialist staff to meet our ambitious project goals. Key goals Catalogue: Reunite Nicholas Crouch's library, creating bibliographic records to international standards for its 4000 early printed titles. Reveal the wealth of unique manuscript material within Crouch's collection through full antiquarian copy-specific notes for his printed books and archival records for his 11 manuscripts. Create the framework for future digitisation. Conserve: Stabilise the text-blocks and bindings to prevent loss of information and allow the volumes to be accessed for digitisation, exhibition, research, teaching and outreach. Box items and move them to PD5454 compliant, secure storage. Communicate: Promote the resources and knowledge created by the project to a wide range of audiences especially in the medical humanities.

Amount: £79,632
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigating the structure and functional role of gut tertiary lymphoid organs in inflammation 02 Mar 2016

Regulatory T cells play a key role in controlling the inflammatory response in the intestine but little is known about their positioning in the tissue in relation to the T effector and antigen presenting cell populations that they control. Tertiary lymphoid organs (TLOs) are organised lymphoid aggregates which are present in gut under homeostatic and inflammatory conditions. Currently little is known about the natural history of TLO’s during the initiation and perpetuation of bacteria-driven intestinal inflammation and their relationship to the antigen specific effector and regulatory T cell response. Here using state of the imaging technologies and novel methods to track bacteria-reactive T cells we will: 1) Characterise the natural history of TLO’s and their relationship to the regulatory and effector T cell response in intestinal inflammation and repair. 2) Use micro-array analysis of total gene expression of TLOs using laser capture microdissection to identify key pathways that control the TLO response. 3) Investigate cell trafficking within TLOs through blocking of known cytokine and receptor pathways using live imaging. These studies will shed light on the functional role of TLO’s in intestinal homeostasis and inflammation, and may identify interventions that manipulate TLO’s as novel therapeutic targets.

Amount: £261,485
Funder: The Wellcome Trust
Recipient: University of Oxford

Dopamine regulation of action initiation and self-control 05 Jul 2016

Dopamine has long been associated with value-guided decision-making, but its precise contribution has remained elusive. One prominent theory elegantly relates the phasic activity of dopamine cell bodies to a prediction error term used in reinforcement learning to represent and update expectations of reward. However, another argues that the functional role of dopamine transmission in terminal fields is to motivate and energise responding. My recent work plots a path to reconcile these perspectives by demonstrating that dopamine release only encodes prediction errors if and when a reward-seeking action is appropriately initiated. Therefore, phasic mesolimbic dopamine release signals the value of action over inaction. My programme will use a combination of complex behavioural tasks and state-of-the-art techniques (fast-scan cyclic voltammetry, optogenetic stimulation, chemogenetic inactivation) to test: (i) whether these signals causally promote actions to be taken, even when actions should be withheld, (ii) what networks are involved in regulating mesolimbic dopamine release in situations when actions should be withheld, and (iii) how mesolimbic dopamine release influences a key foraging decision about whether to act to engage with a presented opportunity. Together, these studies will provide fundamental new insights into the relationship between dopamine release, value and action.

Amount: £1,628,584
Funder: The Wellcome Trust
Recipient: University of Oxford

Functions of the polyamine synthesis pathway in T cell biology 19 Apr 2016

Metabolism is essential for T cell fate and function. This proposal aims to investigate the role of an overlooked aspect of T cell metabolism, the polyamine synthesis pathway. The importance of polyamine metabolism in T cell proliferation, differentiation and function will be characterised using a conditional T cell murine knockout of the master regulator of polyamine synthesis (ODCflox/flox CD4-Cre). Where the polyamine pathway sits in the T cell metabolic network will be investigated in wildtype and ODC-/- T cells using various metabolomic techniques such as Seahorse, proteomics, and analysis of metabolite uptake/usage. How T cells utilise polyamines to drive cell division and differentiation will centre on the ability of polyamines to directly mediate epigenetic modifications and indirectly influence translation through the polyamine-dependent translation elongation factor eIF5a. Analysis of global acetylation/methylation patterns and gene expression in wildtype and ODC-/- T cells will provide insight as to how polyamines influence gene expression relevant to proliferation and differentiation. Similarly, how these molecules influence the translation of proteins also important for cell division and fate will be investigated through proteomic approaches and analysis of translation in ODC-/- and DOHH-/- (an enzyme required for eIF5a activation) T cells.

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

Role of complex synaptic dynamics for learning and memory. 11 Nov 2015

How can real brains learn to perform diverse tasks so much better than supercomputers? One of the reasons is that synapses, the brain's storage medium for experience and memories, are too simplistic in our models. Commonly described only by single numbers denoting their strength, we have ignored the rich internal dynamics of real synapses. By harnessing this complexity, biological systems outperform today's most powerful algorithms. Here, I am proposing a paradigm shift towards complex synaptic models to study their dynamic role for the emergence of computation and memory in neural networks. AIM1: I will design and collaborate on experiments to test fundamental assumptions and predictions from the few existing and adverse theoretical works on complex synapse models. AIM2: Building on these findings, I will create a unifying theoretical framework for complex synapses and fit plausible synapse models to experimental data. AIM3: Finally, I will build biologically inspired spiking neural network models with complex synapses to study self-organization, learning and memory. Using these models, I will generate system-level predictions for experimental verification. Specifically I will collaborate on experiments in flies and mice, suitable for genetic perturbation studies; later on I may include human fMRI studies because of their medical relevance.

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

Franz Kafka's A Hunger Artist: Exploring Anorexia Nervosa on Film 26 Apr 2016

Created through interdisciplinary and artistic collaborations, Franz Kafka’s A Hunger Artist, an adaptation of Kafka’s classic short story, will, in dynamic interplay, depict aspects of anorexic psychology and by contrast, invite vivid experiences of healthy embodiment. It will explore two opposing ways of looking: a voyeuristic gaze that objectifies and spectacularises the body, on the one hand, and a multi-modal, embodied, phenomenological way of relating to images, on the other. The film’s push and pull between these two ways of looking will result in new understandings of anorexia nervosa, as well as new experiences that helpfully run against the grain of anorexia, aiding sufferers to inhabit their bodies in new ways. General audiences will be prompted to feel and think through the question of how media alters a bodily sense of self, for worse and for better. My ethical exploration of these subjects will dialogue with leading edge research across a number of fields. Scientific experts will advise me from perspectives in the neuroscience of affect and embodiment and from the psychoanalytic and psychiatric treatment of eating disorders, as well from Kafka scholarship and first-person perspective. Artistic advisors and collaborators will ensure that our conceptual explorations are aesthetically embedded.

Amount: £39,976
Funder: The Wellcome Trust
Recipient: University of Oxford

Symposium on Drugs, Politics and Society in the Global South 30 Apr 2016

The two-day symposium intends to tackle the issue of illicit drugs through an interdisciplinary, multi-sited approach, which is also peculiar to the tradition of St Antony’s College and the Department of Politics and International Relations at Oxford. The objective is to bring together scholars whose interest in drug politics, sensu lato, and area expertise can contribute to triggering meaningful comparative debate. By focusing on several themes in two days, this would allow a comprehensive discussion of major aspects of drug policy around the world. One major contribution of this symposium would be to discuss the issue of drugs in those regions, which have often been left out of the international drug policy debate. Apart from scholars working on Latin American drug politics, the events will include participation of scholars working on the Middle East, Russia, Africa and China. This would fit the area studies vision that is peculiar to the hosting college, St Antony’s, which is known to have a strong international perspective. Similarly, it will allow reserachers from the Department of Politics and International Relations to attend and participate in the event, thus injecting new analytical and investigative input into the ongoing themes of research existing in Oxford.

Amount: £5,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Interaction of the RNA binding protein Spen with Xist RNA 01 Apr 2016

My research will look into the role of the transcriptional repressor Spen in X inativation. Spen has already been found to be associated with the long non-coding RNA Xist that is known to mediate X inactivation by coating the surface of the inactive X chromosome. The nature of the interaction of Spen with Xist has not been investiagted in detail - the goal of my project is to characterise this interaction. My project will examine the importance of an RNA recognition motif (RRM) domain on the Spen protein, investigating its role in Xist binding. I will generate a mutant construct of Spen with the RRM domain of interest deleted, and examine its colocalisation with Xist. Xist will be expressed from an inducible promoter. The results of my project will generate data that will help to ascertain the importance of the RRM of Spen for Xist binding, helping to provide insights into the mechanism of X inactivation.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural insights into the Rifin protein family of the malaria parasite 01 Apr 2016

Members of the RIFIN family of Plasmodium falciparum are expressed on the surfaces of infected erythrocytes, where they are one of the few surface protein families exposed to the host immune system. They are members of a broader protein family, including the stevors, virs and pirs that are expressed across malaria parasites. This project aims towards the structure of the extracellular domain of a rifin protein, which will allow us to understand the architecture of this entire family of proteins. It also aims to understand the molecular basis for the interaction of a rifin with a novel class of antibody molecule with a LAIR1 insertion and to the molecular basis for the interaction of a rifin with a blood group A antigen. These studies will help us to understand the role of this enigmatic Plasmodium surface protein family that have been implicated in disease severity.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Viet Nam Major Overseas Programme core grant renewal 2015-2020. 21 Apr 2015

Our vision for the Viet Nam Major Overseas Programme is to perform world-leading clinical research with a major impact on local and global health. We will lead a research-driven response to the major and rapidly evolving challenges to healthcare in Asia. We will build regional scientific capacity through a unique and synergistic network of research units, led by the Oxford University Clinical Research unit in Ho Chi Minh City and Hanoi, Viet Nam, and incorporating the Eijkman-Oxford research unit in Jakarta, Indonesia, and the Patan-Oxford research unit in Kathmandu, Nepal. After a decade of development and research diversification, the programme will place emphasis on increasing the impact of our science, the quality of our research, and the efficiency of our operations. Our core research themes will make defining contributions to the understanding of infectious diseases transmission and susceptibility; will develop new tools to prevent, control and treat antimicrobial resistant organisms; will improve clinical outcomes of the major endemic and emerging infectious and non-infectious diseases; and will enhance public health policy in the region. Our unparalleled network of units, partnerships and collaborations, developed over time and spanning every level, enable us to remain ambitious and to deliver world-class research across these themes.

Amount: £16,671,343
Funder: The Wellcome Trust
Recipient: University of Oxford

Genome scale genetic tagging and protein localisation in Trypanosoma brucei . 11 Jun 2015

Our objectives are: 1) Acquire localisation data for the majority of the proteins expressed in Trypanosoma brucei 2) Curate the localisations using established keywords to construct a searchable database accessible through TriTrypDB 3) Assess the morphological phenotype of the cells expressing the tagged proteins 4) Create an interactive image viewer of the localisation database based on the Human Protein Atlas (http://www.proteinatlas.org/) 5) Enable the development of targeted, sophisticated smart assays to interrogate complex biological questions This project is made possible because of a new, tractable PCR-based genetic tagging technology. An amplicon encoding an eYFP tag and a resistance gene is targeted to the desired locus for homologous recombination by sequences incorporated into the PCR primers. The resulting cell lines that express an eYFP fusion protein are imaged and the localisation of the fusion protein subsequently categorised. This is most effect ive way of producing this genome-wide dataset. The localisation database will be an extensively used resource that will facilitate and stimulate research in the trypanosome field and the wider parasite scientific community. This application is focussed, timely and well supported by both the UK and the international research community.

Amount: £709,168
Funder: The Wellcome Trust
Recipient: University of Oxford

Sub-Saharan African Network for TB/HIV research Excellence (SANTHE) 05 May 2015

We will create a sub-Saharan African network of African-led research in HIV (particularly acute HIV (AHI)) and Tuberculosis (TB) infection, which will shape and drive locallyrelevant basic, clinical and translational research in Africa. Our four institutional partnersare all well-established sites: the KwaZulu-Natal Research Institute for TB and HIV (K-RITH) and the University of KwaZulu-Natal (UKZN) (South Africa), the Rwanda-Zambia HIV Research Group (RZHRG) (Rwanda and Zambia), the KEMRI-Wellcome Trust Research Programme (KWTRP) (Kenya), and the Botswana-Harvard AIDS Institute Partnership (BHP) (Botswana). K-RITH/UKZN and RZHRG have been collaborating as part of the Canada-sub Saharan Africa (CANSSA) HIV/AIDS network; and K-RITH/UKZN, RZHRG, KWTRP, and our collaborating partners for this grant, the University of Nairobi (Kenya), the Uganda Virus Research Institute (UVRI)/IAVI site (Uganda), and Aurum Institute (South Africa) have collaborated through an AHI network. New collaborating partners include: University of Rwanda, University of Zambia, and University of Botswana. Our group combines world-renowned expertise in heterosexual HIV transmission in discordant couple cohort studies in Zambia and Rwanda, TB in Botswana and South Africa, AHI studies in female and male cohorts in South Africa and Botswana, and homosexual cohort studies in Kenya. These existing research programmes are supported by long-term partners: Emory University, Harvard University, Oxford University, University College London, Einstein College of Medicine, University of Washington, Amsterdam University, Oregon Health Sciences University, Simon Fraser University and Hamburg University. Our programme strategy targets: 1. Expand on a cuttingedge HIV and TB research programme that includes basic, clinical and translational research. 2. Foster an innovative training and capacity building programme, to develop knowledge and skills for the next generation of African researchers across all institutional partner sites. 3. Facilitate a strong institutional network for research excellence as a pathway to intellectual andfinancial independence for African researchers and their institutions through pilot grants, infrastructure support and administrative support. 4. Create a programme for clinical studiesand community engagement to ensure meaningful translational research and public health and community impact. Our Network will aim to strengthen South-South partnerships, create enabling environments for excellence in research in Africa and train the next-generation leaders of African science. This consortium is specifically focused on HIV and TB as this syndemic' is a public health crisis in Africa that requires the full weight of basic science, translational/clinical research, and political and social mobilization. Although 5% of the world's population lives in Eastern and Southern Africa, they are home to approximately 50% of the world's population living with HIV. 2011 figures list the following prevalence rates in the countries participating in this grant: Kenya 6.2%, Uganda- 7.2%, Zambia- 12.5%, Botswana 23.4%, Rwanda 2.9%, and South Africa 17.3%. As a direct result of the HIV epidemic, TB is now devastating many countries in sub-Saharan Africa. The World Health Organization (WHO) Regional TB statistics for 2012 lists Africa with the highest incidence of 2,300,000 for a population of 892,529,000. HIV can no longer be studied in isolation, and specific research capacity in HIV-TB coinfection also needs to be developed.

Amount: £68,564
Funder: The Wellcome Trust
Recipient: University of Oxford

Memory and motivation in human health and disease 05 Apr 2017

Many brain diseases are associated with disabling cognitive and behavioural syndromes, which are currently poorly understood and have few effective treatments. Here, I propose that we need a systems level account to develop new therapies which target syndromes at the systems or network level, across diseases – regardless of underlying pathology. To test this transdiagnostic approach, I focus on two model syndromes: one cognitive (short-term memory deficits) and the other behavioural (apathy or lack of motivation). My aim is first to deconstruct the cognitive and behavioural components underlying these syndromes using carefully designed, sensitive behavioural measures. Then to relate behavioural performance to brain networks using a multimodal neuroimaging approach, including structural and functional connectivity measures. To identify whether there are robust brain imaging signatures of component deficits that are common to different diseases, we shall examine patients with Alzheimer’s disease, Parkinson’s disease, stroke and small vessel cerebrovascular disease. To determine whether we can detect these signatures at the earliest stages of disease (in their preclinical phase) we shall apply these methods also to groups at high risk of developing neurodegenerative disorders. Finally, we shall examine whether it is possible to modulate component deficits using cholinergic and dopaminergic drugs.

Amount: £2,351,566
Funder: The Wellcome Trust
Recipient: University of Oxford

The MYRIAD Project: Exploring Mindfulness and Resilience in Adolescence 30 Jun 2017

The MYRIAD Project: Exploring Mindfulness and Resilience in Adolescence

Amount: £250,800
Funder: The Wellcome Trust
Recipient: University of Oxford

Public Engagement for the Thailand Major Overseas Programme 2015 – 2020 (supplement) 30 Sep 2017

The Wellcome Trust Thailand Major Overseas Programme’s central aim is to improve health and reduce the human disease burden in the developing world. Its strategic objectives are: The development of people and institutions: mentoring world-class clinicians and scientists Disseminating high-quality research evidence, locally and globally Strengthening governance, management and financial planning, thus building operational excellence in tackling tropical diseases Public engagement (PE) & outreach with the communities who host us, in turn inspiring and involving current and future generations in medical research This application pertains to the last strategic objective of the programme. The "must-do" engagement activities are part of the Thailand Major Overseas Programme core grant 2015 -2020. In April 2016, the programme received a PPE award (£673,180) to build a core PE team and to pilot some "smart-to-do" and "wise-to-do" activities in years 1 and 2 of the core grant and with a view of shaping the PE activities for years 3 to 5. The core PE team is led by Ass. Prof. Phaik Yeong Cheah, who is co-PI on this application. This application is for PE activities in years 3 to 5 based on learnings from our pilot projects and to grow further the PE capacity within the programme.

Amount: £454,843
Funder: The Wellcome Trust
Recipient: University of Oxford