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Recipients:
University of Oxford

Results

Cognitive Factors in Adjustment to Social Trauma 30 Sep 2016

Socially traumatic events that may include rejection or humiliation in the context of bullying can have lasting and debilitating psychological effects. This project will investigate the nature of these effects, explore maintaining mechanisms of psychopathology, and develop and pilot a specific intervention to improve functioning in adults suffering after experiencing social trauma. It will build on cognitive models and existing treatments for posttraumatic stress disorder (PTSD) and social anxiety disorder (SAD). First, there will be a detailed investigation of social trauma and its effects in young people using surveys, interviews, and secondary analyses of cohort data. Negative effects may include intrusive memories, negative appraisals of self and others, safety behaviours, and disrupted post-event processing. The nature of psychopathology related to social trauma will be validated against existing measures of PTSD, SAD, and depression. A series of experimental studies on appraisals of social threat and qualities of social interactions will distinguish those struggling more and less severely after social trauma and fulfil the second goal of identifying maintaining mechanisms. The final goal is to develop and evaluate a procedure for updating problematic social trauma memories in a pilot case series. Overall, this project will help improve psychological treatments following social trauma.

Amount: £247,640
Funder: The Wellcome Trust
Recipient: University of Oxford

Targetting optogenetic constructs to retinal ON-Bipolar cells 30 Sep 2016

"How best can optogenetic constructs be targeted to retinal ON-Bipolar cells to restore functional vision?" This project aims to use the human photopigment melanopsin to induce light responses in retinal ON-bipolar cells (optogenetics) of a mouse model, blind from retinal degeneration, in order to restore functional vision. This comprises three key goals: Goal 1 "When" To further describe changes in bipolar cells over time during retinal degeneration in terms of their gene expression and association with other cells in the mouse model. Goal 2 "What" To determine if melanopsin - or an alternative construct (Channel Rhodopsin - ChR2) - is more efficacious in restoring functional vision. Quantified:- At a cellular level (Calcium imaging, Electrophysiology) At an organism level (Behavioural paradigms) Goal 3 "Where" To determine if bipolar cells – or an alternative target (retinal ganglion cells) - are more efficacious in restoring functional vision by melanopsin expression (quantified as in goal 2). The eventual purpose of these goals is, along with parallel work, to develop an application to the Gene Therapy Advisory Committee (GTAC) to conduct a clinical trial to restore functional vision in patients blind from inherited retinal degenerations.

Amount: £285,040
Funder: The Wellcome Trust
Recipient: University of Oxford

Functional genomics of malaria sporozoite - host hepatocyte interactions 18 May 2016

Intensive study of the ligand-receptor interactions by which malaria merozoites invade erythrocytes has yielded promising vaccine and drug targets. In contrast, there is little understanding of the process by which malaria sporozoites invade hepatocytes, despite the fact that antibody-inducing sporozoite-targeting vaccines are the leading approach to malaria vaccine development. I propose to use the following recently developed and complementary techniques to systematically elucidate ligand-receptor interactions involved in this process: 1. Biochemical identification of ligand-receptor interactions using an existing library of pentameric P. falciparum sporozoite proteins to probe plate-anchored recombinant hepatocyte surface proteins. 2. Genetic identification of receptors essential for in vitro hepatocyte invasion using a CRISPR-Cas9 gene-disruption strategy. A lead panel of 100 abundant candidate receptors will be selected using existing proteomic data, with potential for extension to the complete hepatocyte surface proteome. Identified interactions will be validated via host and parasite manipulations (gene disruption and antibody blockade), both in vitro using primary hepatocyte cultures and in vivo, including use of a humanized mouse model of P. falciparum liver-stage infection. As has been the case for study of merozoite-erythrocyte interactions, I anticipate the project will provide the basis for rational approaches to malaria prophylaxis via disruption of the identified interactions.

Amount: £414,492
Funder: The Wellcome Trust
Recipient: University of Oxford

The demand for prevention in middle and later life 18 Jul 2016

Population ageing is likely to increase the burden of non-communicable diseases (e.g. cancer). Prevention (including health behaviour and screening programmes) can considerably reduce the morbidity and mortality risks of these diseases, and will therefore play a key role in maintaining the health of an ageing population. The research project will investigate the demand for prevention among middle-aged and older people theoretically and empirically. In the first part of the project, I will derive a theoretical framework based on the health capital model that allows me to derive hypotheses on determinants of the demand for prevention, in particular with respect to time costs. In the empirical part of the project I will test these hypotheses using econometric methods for causal inference and data from the UK as well as international data. I will analyse three specific factors that are associated with different levels of time costs and play a major role among older people – retirement, informal care provision and voluntary work. The projected output will consist of at least four academic papers and a number of conference presentations. I will engage members of the public in an advisory group. Keywords: prevention, screening, health behaviour, causal inference, ageing

Amount: £176,150
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

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

Linking MRI and microscopy for multi-scale neuroscience: Mechanisms, diagnostics and anatomy 05 Jul 2016

MRI has tremendous potential to provide diagnostic and mechanistic insights into brain health and disease in living subjects, but is limited by its poorly defined relationship to histology. My group has pioneered techniques for combining MRI and histology that will enable us to define these relationships to provide more biologically interpretable MRI measures. We will construct models relating MRI and histology both from the bottom up (using microscopy to predict MRI signals) and top down (predicting histopathology from MRI). The top-down approach will use machine-learning methods to predict histological stains from in-vivo MRI, providing "virtual neuropathology" for improved diagnosis in living patients. The bottom-up approach will use electron and optical microscopy for hyper-realistic predictions of the MRI signal with the goal of identifying novel MRI signatures relating to mechanisms of neural health and disease. My group is poised to leverage our unique expertise within a comprehensive research program spanning scales (microscopic to macroscopic), species (rodent to humans) and expertise (physics to neuroscience). We will deploy these methods with neuroscience collaborators for: (i) virtual neuropathology in ALS; (ii) mechanisms of experience-induced plasticity; and (iii) high-resolution neuroanatomy. A primary output will be the "Oxford Digital Brain Bank", a freely available data repository.

Amount: £1,793,980
Funder: The Wellcome Trust
Recipient: University of Oxford

Characterising neural networks of thalamo-cortical interactions important for cognition. 02 Dec 2015

Complex cognition arises in distributed and integrated brain networks. Animal models have shown the critical importance of the magnocellular subdivision of mediodorsal thalamus (MDmc) to cognitive processes via its cortical interactions. Neuroimaging of several neuropsychiatric diseases has also highlighted changes in the connectivity of MD and cortical interactions. Yet critical knowledge about how the MDmc and cortex communicate effectively in cognition remains unknown. One of the key goals of this research will determine the origins and synaptic characteristics of cortical driver inputs of MDmc (i.e. those cortical inputs that are capable of transmitting a message via the transthalamic MDmc route to other cortical areas). This goal will be achieved by combining neuroimaging, immunohistochemistry and immuno-electron microscopy to understand which cortical areas relay messages via the MDmc neural networks. Further, we do not know what the messages are being relayed via the MDmc to other cortical regions and how they are important for cognition. Thus the other key goal of this research is to investigate what the messages are, relayed via the MDmc using cognitive testing, electrophysiology, and discrete manipulations to MDmc and interconnected cortical regions. The overall aim of this goal is to establish how communication between the MDmc and cortex is important for learning new information and decision-making. Neuroimaging in thalamic stroke patients and healthy controls will provide an additional step in advancing fundamental knowledge about the critical importance of communication between subcortical-cortical integrated networks in cognition.

Amount: £2,329,340
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural cell biology of bacterial biofilm formation 01 Jun 2016

The last few years have seen dramatic developments in the field of electron cryomicroscopy (cryo-EM). Cryo-EM allows imaging of biological material at multiple scales, from purified macromolecules to whole cells. Now with the latest direct electron detector technology coupled with novel image processing algorithms, near-atomic resolution structures may be resolved using cryo-EM. Biofilms are surface associated bacterial communities that play a role in many infectious processes. The goal of my research is to use the latest electron microscopy technology to image bacterial biofilms at high-resolution. I will focus on two opportunistic pathogens - Escherichia coli and Pseudomonas aeruginosa for my research. Infection from both these bacteria relies on colonization of specific niches in the human body with the formation of biofilms. I will solve structures of molecules mediating biofilm formation using cryo-EM, describe the cellular location of these molecules using electron cryotomography, and place these data into context by imaging entire biofilms, also using electron microscopy. I will produce a molecular resolution description of bacterial biofilms, which when combined with near-atomic resolution structures of key molecules, will yield a three-dimensional understanding of bacterial biofilms in unprecedented detail leading to deep mechanistic understanding of this important bacterial developmental process.

Amount: £1,135,857
Funder: The Wellcome Trust
Recipient: University of Oxford

Optical Interrogation of Sub-Cellular Cardiac Signalling in Atrial and Sino-Atrial Node Arrhythmias At High-Spatiotemporal Resolution. 21 Oct 2015

Atrial fibrillation (AF) is the most frequently encountered arrhythmia, associated with increased morbidity and mortality. It is known that lysosomes are actively involved in cardiac calcium regulation. I hypothesize that calcium contribution from the lysosomes is important in atrial function and perturbations in lysosomal calcium in disease processes can lead to AF initiation and/or maintenance. I propose a multi-faceted study to investigate sub-cellular anatomy, especially spatial localisa tion of organelles, and the role of lysosome mediated calcium signalling in normo- and patho-physiology. Along with pharmacological interventions, we will develop optogenetic probes to specifically control lysosomal calcium release to investigate these mechanisms. On the mechanistic side,the aim is to develop a new imaging method capable of measuring cellular and subcellular calcium events in 3D. This will be validated using cell culture models and high-speed optical mapping, which can be manipu lated to investigate arrhythmogenesis. Using fixed tissue from healthy/AF, we will perform proteomics and structural studies (MRI, electron microscopy).This will inform pharmacological and tissue engineering methods for more focussed research. The results from this study will allow a better understanding of the basic biological mechanisms of sub-cellular calcium signalling and the aetiology of AF directly relevant in the development of new treatment therapies.

Amount: £752,493
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

Metabolic control of T cell receptor signalling 11 Nov 2015

T cell receptor (TCR) activation is essential for the effector functions and proliferative potential of T lymphocytes. Optimal TCR responsiveness requires assembly of the TCR signalosome, a super-molecular signaling complex that couples external antigenic cues to intracellular biochemical events. I discovered that spontaneous activation of the metabolic master regulator AMPK induces loss of the TCR signalosome from human senescent T cells, a novel hallmark of human ageing. This suggested the exi stence of an unrecognized link between changes in T cell metabolism and TCR responsiveness. I also identified cross-talk between AMPK and p38 MAPK signaling that regulates both senescent features and metabolic demands of T cells. Whether intervention at the point of energy sensing pathways may restore TCR functional activity in senescent T cells is not known. Here I propose that the modulation of metabolic pathways by disrupting the AMPK-MAPK signaling axis would restore TCR function. Restoring TCR responsiveness in senescent T cells would offer novel ways to recover T cell activity among the elderly population that suffers from increased susceptibility of opportunistic infections and cancer. Furthermore, since T cells undergo metabolic impairment during an immune response, these studies may have relevance for boosting non senescent T cell responsiveness in vivo.

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

Scoping and Collaboration Exercise for Epilepsy Research in Zimbabwe 31 May 2016

This application requests funds for two speakers from Zimbabwe to attend a conference I am co-organising at St Antony's College, Oxford. The theme is Health and Politics in Zimbabwe and the Diasporas. The Research Day will examine the politics of health provision, health culture, change and development, exploring history, practice and impacts. The experiences of Zimbabwean health professionals abroad will be a key part of the conversation. The day will include a mix of well-known and up and coming researchers and practitioners, academics and non-academics. It will be a forum for debate, shared experiences, new research and future thinking. My invited speakers are contacts working in Zimbabwe on 1) health policy and 2) epilepsy. I have conducted a 2 week pilot visit to Zimbabwe in order to identify field sites for a larger grant application on the history of epilepsy in Africa. Both of these contacts will be instrumental for future research. In addition to the Oxford conference, I will organise meetings for the speakers with researchers interested in mental health and epilepsy in Zimbabwe/Africa, as well as visits to the Wellcome Unit for the History of Medicine, Oxford, Wellcome Library in London, Epilepsy Research UK and Epilepsy Action, London.

Amount: £2,706
Funder: The Wellcome Trust
Recipient: University of Oxford

Workshop: Human evolution in structured populations 30 Apr 2016

Understanding the origins and early demographic history of our species has wide ranging implications for the medical, social and biological sciences. Until recently, consensus for a single East African centre of endemism for Homo sapiens was widespread. However, archaeological, fossil and genetic data increasingly suggest that the emergence of our species occurred within a set of subdivided populations located across Africa, rather than within a small and isolated East African population. The complexity of our origins is further emphasised by admixture with archaic Homo species in Eurasia and possibly even in Africa itself. This notwithstanding, competing models of ours origins remain to be evaluated within an interdisciplinary context invoking evidence for intra-African dispersals, population size and structure. Instead, research on the origins and early demographic history of Homo sapiens remains frustratingly disjointed, with often-incompatible jargon and methods of data analysis. In this workshop, archaeologists, geneticists, palaeoanthropologists and related specialists will forge integrated, interdisciplinary models explaining the often-contradictory evidence gleaned from different sources of data. The workshop will begin with a public symposium followed by two days of discussion and debate, permitting the development of a new, integrated data hypotheses of the processes culminating in today’s cultural and biological diversity.

Amount: £5,000
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

Structural insights into the link between GATA2 and acute myeloid leukemia (AML). 01 Apr 2016

Acute myeloid leukaemia (AML) is a blood-related disease characterised by the uncontrolled proliferation of haematopoietic stem cells lacking the ability to commit to normal differentiation. It is highly malignant, with only a 25% survival rate 5 years after diagnosis, despite intensive therapeutic treatments. GATA2 is a zinc-finger (ZnF) transcription factor broadly expressed in haematopoietic stem cells (HSCs). GATA2 is necessary for maintenance of a regenerative HSC pool as well as lineage-restricted differentiation. Given this, it is perhaps unsurprising that GATA2 mutations have been linked with AML. Currently, little is known about the mechanism of GATA2 function in leukaemias. GATA2 contains 2 ZnF domains (NF and CF), which have been shown to bind different DNA motifs and protein partners in vivo. I postulate that these interactions are necessary for the biologial activity of GATA2, and will attempt to show that mutations in the NF and CF domains result in loss of this activity. This will be achieved by using a combination of methods including bioinformatics, molecular docking and in vitro biophysical studies using generated GATA2 mutants. This research aims to show that GATA2 mutants deregulate HSC proliferation by virtue of altering its ability to interact with cognate partners.

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

Oxford part of Kenya MOP renewal 2010 - 2015. Transfer to Philip Bejon. 22 Jun 2015

This proposal is for core funding for an integrated programme of health research conducted in East Africa through the KEMRI Wellcome programme. Core funding supports the essential infrastructure and personnel to provide a platform on which the specific research components, are built. The research programme it self is embedded in a national research institute (KEMRI) but has collaborative links to a large number of governmental, educational and research institutions in Kenya and the East A frican region . The research programme is conducted by 32 principal investigators, funded by competitive research grants and fellowships, working closely together under four main disciplines: (1) Clinical Sciences (2) Epidemiology, Demography and Public Health (3) Pathogen Biology (4) Health Systems and Social Science Research. For the period 2011-2016 the programme has four key strategic scientific themes: Improving child survival during a period of rapid epidemiological transition Ad dressing adult health focussing on maternal health and recognising the impact of HIV on vulnerable populations Strengthening health systems through research on policy for, access to, monitoring, evaluation and delivery of care. Applying basic science to develop new interventions to realise the enormous potential of new technologies in the post genomic era.

Amount: £16,433,919
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