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Recipients:
University of Oxford
Award Year:
2016

Results

A Public Engagement package to support research towards reductions of antimicrobial usage in farming systems in the Mekong Delta of Vietnam (Intermediate Clinical Fellowship Grant No. 110085/Z/15/Z). 27 Dec 2016

The ViParc project (Vietnamese Platform for Antimicrobial Reductions in Chicken Production) started in March 2016. Relevant research staff (project coordinator and laboratory coordinator, both based in OUCRU) have been recruited. Permissions from the Provincial People’s Committee and Sub-Department of Animal Health in the Mekong Delta province of Dong Thap (SDAH-DT) have been granted. A detailed budget has been drafted and agreed with SDAH-DT. A planning meeting was successfully held on 22nd June 2016 in Ho Chi Minh City with participation of all project partners (including the Royal Veterinary College, Institute of Poultry Diseases and University of Can Tho). A visit to SDAH-DT was carried out to identify potential project veterinarians and to provide them with training on post mortem techniques for poultry (led by Prof. Hafez). Laboratory equipment to carry out testing of antibiotic residues in meat has been purchased and installed in OUCRU, and training has been provided to the laboratory coordinator. A website has been launched to inform about ViParc project activities (www.viparc.org). This has a designated Public Engagement section. A number of field equipment items have been purchased and delivered to SDAH-DT. All forms and SOPs have been developed, as well as a database to capture both laboratory and field data. A meeting with SDAH-DT to discuss setting up the CABs is arranged for mid-September.

Amount: £75,979
Funder: The Wellcome Trust
Recipient: University of Oxford

Human sensitivity to short-wavelength light in non-image-forming vision: Toward a mechanistic understanding of the impact of blue light on sleep and circadian rhythms 09 Nov 2016

Short-wavelength (blue) light takes priority in many functions associated with the non-image-forming (NIF) visual system, including pupil size and regulation of melatonin secretion. The human retina contains two short-wavelength sensitive photoreceptors: the blue-sensitive (S) cones (~440 nm) and the recently discovered photopigment melanopsin (~480 nm) expressed in a subset of retinal ganglion cells. Previous research has focused on the melanopsin contributions to NIF responses, but very little is known about how S cones contribute to and interact with melanopsin in these functions. Using the method of silent substitution which allows for the selective isolation of photoreceptor classes and by studying patient groups with S-cone anomalies, we will study the S cone and melanopsin inputs into pupil control and circadian mechanisms. In Aim 1, S cone and melanopsin inputs into the pupil will be characterised in controls and S-cone patients and related to sleep-wake actigraphy. In Aim 2, the spatial topography of S cone and melanopsin pupil inputs will be characterised using a novel spectral-spatial modulator. In Aim 3, S cone and melanopsin inputs into melatonin suppression will be characterised. In short, we will systematically characterise the receptor mechanisms that mediate the effect of short-wavelength light on circadian regulation in humans.

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

A dynamic approach to sensory processing in autism 09 Nov 2016

The importance of sensory symptoms in autism is clear, but we do not yet understand why they occur. Previous research has concentrated on the end-point of sensory processing, failing to consider the dynamic process and confounding multiple stages leading to atypical responses. It is therefore unclear whether autistic individuals show altered accumulation of sensory evidence and/or altered decision bounds. This Fellowship will characterise better sensory processing in autism, with three objectives. First, I will pinpoint the mechanisms of sensory processing differences by quantifying sensory and decisional parameters and their relationships with action. Second, I will investigate how these parameters relate to everyday sensory symptoms in autism. Third, I will assess whether co-occurring symptoms moderate sensory processing differences in autism. I will use a model-based cognitive neuroscience approach. Autistic and typical children will make decisions on sensory stimuli while electroencephalography (EEG) is recorded. I will use hierarchical drift-diffusion models to jointly model behavioural and neural data to identify the components of sensory processing affected in autism. I will relate these components to parent-reported sensory symptoms and co-occurring symptoms. I will use Bayesian statistics to ensure the robustness of my findings. The findings will help to guide the design of future interventions.

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

Core award for the East African Major Overseas Programme - KES portion 30 Jun 2016

Our application provides the platform for a uniquely inter-disciplinary scientific programme linking biomedical, social and health systems research to deliver scientific insights of global importance to human health. We will work based from Kenya (Kilifi and Nairobi) and Eastern Uganda (Mbale). The Kilifi Programme will tighten its focus on our integrated platform (i.e. linked hospital/demographic/molecular surveillance) and legacy of continuous epidemiological data and stored samples over 25 years. Work in Mbale will consolidate a leading centre of clinical investigation in an area of hyper-endemic malaria transmission, and the Nairobi Programme will increase its independence with a focus on international disease mapping and health systems. Our major scientific themes include vaccines (including pre and post-licensing studies with exploratory immunology and epidemiological components), genomics and infectious disease transmission, clinical research (focusing on multi-centre clinical trials and the pathophysiology of critical illness with a developing programme on neonatal and maternal health), public health (with an emphasis on spatio-temporal analyses) and health systems research. The Programme is delivered by 29 PIs (i.e. scientists with independent funding). Training is central to our vision, and additional awards support 18 post-doctoral scientists and a projected 50 PhD students during the next 5 years.

Amount: £18,904,756
Funder: The Wellcome Trust
Recipient: University of Oxford

Defining mechanisms for pancreatic beta-cell dysfunction in type 2 diabetes 05 Apr 2016

The over-arching aim of my research vision is to identify effective therapeutic targets for type 2 diabetes (T2D) treatment through mechanistic studies of proteins causally implicated in T2D risk by human genetics. To achieve this I plan to capitalise on my ability to work at genome-scale to unlock the effector transcripts at genome-wide association study loci and to use state-of-the art genomic techniques in recently developed human beta-cell models to understand what these proteins do in beta-cells, how they contribute to defects in insulin secretion, what networks they are involved in and how we can leverage this new knowledge to identify therapeutic targets.

Amount: £2,329,169
Funder: The Wellcome Trust
Recipient: University of Oxford

Dynamic cortical networks for cognitive flexibility 19 Apr 2016

This project will test the neural basis of cognitive flexibility. Cognitive flexibility allows us to change the rules governing our behaviour to fit the current context. Flexibility is important because we need it even for common tasks, such as changing our normal route home to stop by the supermarket. Prefrontal cortex (PFC) is necessary for cognitive flexibility: damage leads to severe impairments. However, the functional mechanism is largely unknown. I propose that flexible rule switches are implemented through dynamic changes in functional connectivity within the PFC and across the brain. Connectivity sub-selects a local PFC ensemble and links it to appropriate input and output regions, ensuring that new input triggers a state-dependent cascade of neural activation that underpins context-appropriate action selection. I will test whether oscillatory synchronization within PFC and across context-relevant areas is central to this dynamic coding of flexible rule switches by combining multivariate analysis and computational modeling with recordings from animals and humans (intracranial recordings and MEG). Both dynamic coding and synchronization are fundamental building blocks of neural coding. Therefore, synthesizing these ideas in a coherent framework would be of wide interest in systems neuroscience and psychology.

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

Identification of interferon-stimulated antiviral genes that contribute to the HIV-1 transmission bottleneck 01 Apr 2016

Identification of immune mechanisms of HIV-1 control at mucosal transmission sites is of importance to facilitate the development of strategies to block infection prior to systemic virus spread. My host lab have shown that HIV-1 transmitted founder viruses are relatively resistant to type I interferon (IFN)-mediated antiviral activity (as compared to viruses replicating in chronic infection), suggesting that type I IFNs make an important contribution to the HIV-1 transmission bottleneck. This project will contribute to ongoing work aiming to identify the IFN-stimulated antiviral genes that drive the IFN-resistance of founder viruses. My first aim will be to confirm preliminary results indicating that high concentrations of type II and III IFNs also inhibit HIV replication and that founder viruses are relatively resistant to their activity; and to test the effects of lower IFN concentrations. Findings from these experiments together with results from the lab’s microarray and qPCR-based analysis of common/differential gene up-regulation by high/low concentrations of type I, II and III IFNs will then be employed to identify genes to which founder viruses may be preferentially resistant. My second aim will be to use siRNA knockdown to test the role of 1-2 selected genes in founder virus IFN-resistance.

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

Using parasite population genomics to improve understanding of malaria epidemiology 30 Nov 2016

This collaborative project will use genomic approaches to characterise demographic flux and evolutionary trends in the malaria parasite population. Using novel methods for parasite genome sequencing that are suitable for large-scale field applications, we will perform longitudinal studies of parasite population genomics at multiple locations with different transmission intensities in Africa and Southeast Asia, and we will examine the clinical and epidemiological correlates of population genomic variables under a range of ecological settings. We will develop statistical and computational approaches to use longitudinally sampled genome sequencing data to construct spatial maps of parasite demography and examine how this changes over time. We will promote collaboration between experts on population genomics, geospatial mapping and mathematical modelling to use these data to inform and improve epidemiological models of malaria transmission. Our overarching goal is to establish the practical and analytical foundations to use parasite genome sequencing to investigate the causes of epidemiological events such as resurgence and emerging drug resistance, and thus to assist in planning effective interventions.

Amount: £3,989,275
Funder: The Wellcome Trust
Recipient: University of Oxford

The translational potential of mass spectrometry and next-generation sequencing in patients with central nervous system infections in Vietnam 22 Nov 2016

Central nervous system (CNS) infections are devastating conditions worldwide, especially in low- and middle-income counties (LMIC). Clinical outcomes are dependent upon the rapid identification of the causative agent and instituting effective antimicrobial therapy, although the causative agent is only identified in This Fellowship will focus on the translational potential of mass spectrometry and next-generation sequencing (NGS) in clinical diagnostics of CNS infections in Vietnam, and has three key goals: To determine whether Mass spectrometry of cerebrospinal fluid (CSF) will identify protein/peptide signatures associated with different infectious aetiologies. To determine whether NGS-based metagenomic analysis will identify a broad range of known/unknown pathogens in the CSF and improve upon current standard laboratory assays. To determine whether NGS can provide rapid, whole genome sequence-based prediction of antimicrobial susceptibility for Mycobacterium tuberculosis and Streptococcus pneumoniae. I aim to provide proof-of-principle that CSF proteomics- and NGS-based methods can improve upon the diagnostic assays currently available in hospital settings, especially in LMIC, and thereby potentially improve patient outcomes.

Amount: £685,086
Funder: The Wellcome Trust
Recipient: University of Oxford

Ultrasonic Delivery of Theranostic Anti-Cancer Agents 19 Apr 2016

Key words: platinum, controlled release, cancer, ultrasound, drug delivery This research develops a powerful new methodology for treating cancer with a highly specific, potent action and markedly lower side-effects, compared with existing therapies. It combines the potency of platinum anti-cancer complexes – encapsulated to prevent unwanted side-reactions – with the selectivity of drug release at a tumour afforded by focused ultrasound. We will synthesise new PtIV prodrugs designed for encapsulation and delivery using ultrasound; a novel approach for platinum drug delivery. Groups will be attached to the PtIV centre to aid tracking both in cellulo and in vivo. Once inside cancer cells, the PtIV complexes will be rapidly converted to PtII by intracellular reducing agents. The resultant PtII fragment is anticipated to form DNA lesions, ultimately inducing cell death. The PtIV prodrugs will be liposomally encapsulated, and the liposomes attached to large gas-filled microbubbles, creating a drug delivery vehicle. Ultrasound – focused at the site of a tumour – will destroy the vehicle, releasing the prodrug and enhancing the penetration of the prodrug into the tumour. We will investigate PtIV prodrug characterisation, release from the delivery vehicle, cellular uptake, reduction to PtII species, cellular distribution and cytotoxicity.

Amount: £351,122
Funder: The Wellcome Trust
Recipient: University of Oxford

Protein Antibiotics: Discovery, mode of action and development 05 Apr 2016

The rise of antibiotic resistant bacteria poses a catastrophic threat to humanity. Despite the pressing need, few new antibiotics have entered the clinic in the last 30 years. The situation is particularly urgent for multidrug resistant Gram-negative bacteria Pseudomonas aeruginosa and Klebsiella pneumoniae. We will address this problem through the use of bacteriocins, which are species-specific protein antibiotics made by Gram-negative bacteria during environmental stress. We recently discovered that pyocins, deployed by P. aeruginosa to kill neighbouring Pseudomonad spp, are more effective at protecting mice infected with an acute P. aeruginosa lung infection than tobramycin, the leading antibiotic used clinically for the treatment of pulmonary infections. Through this multidisciplinary, multicentre collaborative award, which brings together experts in bacteriocin structure and function (Kleanthous, Walker), pathogen genetics and genomics (Maiden, Parkhill) and animal models of bacterial disease (Evans, Taylor), we will (i) uncover the mechanism(s) by which pyocins translocate across the P. aeruginosa cell envelope, capitalizing on exciting new structural and microscopy data, (ii) investigate the efficacy of pyocins as antibiotics in animal models of disease, and (iii) initiate the first such studies on klebicins, bacteriocins that target Klebsiella pneumoniae.

Amount: £2,151,302
Funder: The Wellcome Trust
Recipient: University of Oxford

An Analysis Of The Animal/Human Interface With A Focus On Low And Middle Income Countries 30 Sep 2016

Fleming Fund: supporting surveillance capacity for antimicrobial resistance The animal/human interface with a focus on low and middle-income counties Stephen Baker – Oxford University Clinical Research Unit, Viet Nam Our core research themes aim to make defining contributions to the understanding of infectious diseases transmission and susceptibility; to develop new tools to prevent, control and treat antimicrobial resistant (AMR) organisms; improve clinical outcomes of the major endemic and emerging infectious and non-infectious diseases; and 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 deliver world-class research across these themes.

Amount: £21,091
Funder: The Wellcome Trust
Recipient: University of Oxford

Assessing the safety of low dose primaquine in Plasmodium falciparum infected African children with glucose 6 phosphate dehydrogenase deficiency 02 May 2016

Malaria remains a major problem in tropical countries, especially in Africa. Insecticide treated bednets and new powerful antimalarial drugs have led to a reduction in the number of malaria deaths. However malaria control remains poor in many areas, and if we are to eliminate and eventually eradicate the disease from the world we will require the use of all the tools at our disposal.One potentially very valuable tool, currently underused, is the antimalarial drug primaquine, which is uniquely able to kill the mature male and female sexual forms of the malaria parasite. Research has shown that primaquine greatly reduces the malaria offspring in the mosquito and thus effectively reduces transmission of the disease. So, primaquine looks to be a good 'transmission blocker' and, if used widely in patients, may reduce malaria transmission and contribute to the elimination of malaria in a community.Unfortunately primaquine has one major disadvantage. It can damage the red blood cells and cause anaemia in individuals who carry a very common genetic abnormality deficiency of an enzyme called glucose-6-phosphate dehydrogenase, G6PD for short. This deficiency is much more common in men because of the way it is inherited. This is called haemolysis. This is a real downside of primaquine, though this problem has mainly been seen when primaquine is given in high doses for many days. However, for its 'transmission blocking' effects on the malaria parasite only a single, low dose of primaquine is thought to be required. This is considered by most experts to be too little primaquine to cause a major problem with haemolysis. Despite this many malaria control programmes are unwilling to use primaquine because they consider it too dangerous. You can test for G6PD deficiency but this requires test kits and staff to administer them. Many countries cannot afford to test millions of malaria patients before giving primaquine. In 2012 the World Health Organization (WHO) concluded on the basis of the available evidence and expert opinion that single low dose primaquine was safe to use even in malaria patients with G6PD deficiency. However the WHO also called for more research.Four years later virtually no one is using low dose primaquine because that research has not been done. If we can show beyond doubt that low dose primaquine is safe in G6PD deficient children with malaria, malaria programmes would feel much happier giving it and we could then go to the drug companies and ask them to make primaquine that is suitable for children.To see if single low dose primaquine is as safe as experts think we plan to study over 1,500 children with malaria attending outpatients in two hospitals in Uganda and one in the Democratic Republic of the Congo. Using a simple test for G6PD deficiency we will find 750 children with malaria who have G6PD deficiency, and 750 who have normal G6PD levels. Within these two groups we will, on a random basis, give half of the patients normal antimalarial treatment and the other half normal antimalarial treatment PLUS single low dose primaquine. We will then watch the children very carefully to see whether giving primaquine causes more anaemia than not giving primaquine, and whether this occurs particularly in the G6PD deficient group. We need to have comparison groups of children who do not receive primaquine and some children who do not have G6PD deficiency as malaria itself causes haemolysis, as can G6PD deficiency in some circumstances even without primaquine treat. Our aim is to unpick the effects of G6PD deficiency, malaria, and primaquine administration to really be sure whether in all circumstances giving low dose primaquine is safe.If this research shows that giving single low dose primaquine is safe, this will enable WHO and national governments to recommend safe treatment regimens that will both cure the patient and also prevent transmission of malaria to other children.

Amount: £363,765
Funder: The Wellcome Trust
Recipient: University of Oxford

RCT to evaluate an intervention for depressed HIV-positive women in the perinatal period, to enhance child development and reduce maternal depression 02 May 2016

Rates of HIV are very high amongst pregnant women in parts of sub-Saharan Africa (SSA) with, for example rates of over 30% in antenatal clinics in South Africa1. Many receive their diagnosis during pregnancy as partof screening to prevent mother-to-child transmission (PMTCT). Depression is very common amongst these women, with up to 40% screening above the threshold for depression2, 3. Perinatal depression is associatedwith poor adherence to antiretroviral treatment (ART)4, 5, low clinic attendance, suicidal ideation6 and lowrates of breastfeeding7. Of major concern is the evidence of negative effects on fetal outcomes, children'sgrowth and cognitive development7. Improving the wellbeing of mothers and infants requires effectivetreatment of HIV and perinatal depression8. Although treatment of depression improves adherence to HIVtreatment by >80% 5, there is no established effective treatment for perinatal depression in SSA for motherswith HIV. The aim of this study is to develop and test the feasibility and acceptability of a six-session intervention targeting perinatal depression in HIV-positive women. The intervention will utilise Behavioural Activation (BA), which has been shown to be as effective as Cognitive Behaviour Therapy (CBT) in high-income settings9. BA is much simpler than CBT to deliver, especially by non-specialist health workers withlimited training in under-resourced settings. This early phase study is needed to develop, standardise and pilot the BA intervention and test its feasibility. The study will provide treatment for 70 pregnant women and follow them to 3 months postnatally. The outcomes of the main study will include: maternal depression, child emotional and cognitive development and growth, adherence to ART, initiation and maintenance of breastfeeding, infant HIV testing and vaccinations. This work will be conducted at the Africa Centre for Health and Population Studies, a large demographic surveillance site in South Africa with a high HIV prevalence.

Amount: £591,322
Funder: The Wellcome Trust
Recipient: University of Oxford

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £3,000,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Inflammation associated modulation of DNA methylation: An investigation into the genetic determinants and transcriptional consequences 18 May 2016

Chronic inflammation is pathologically and genetically implicated in conditions as diverse as Alzheimer’s disease and cancer. DNA methylation helps determine cellular activity and is frequently aberrant in malignancies. Given methylation is sensitive to the environment, understanding the effects of immune activity whilst considering genotype is of high importance. This application proposes to develop unpublished data where I observe stimulation with Toll-like receptor agonists leads to significant, highly delineated, genome-wide changes in monocyte DNA methylation in a genotype dependent manner. Notably, genes frequently mutated in cancer are enriched amongst those displaying immune triggered demethylation, suggesting a direct link between inflammation and mutagenic pressure. I will characterize the pathophysiological importance of these observations by describing the kinetics of differential methylation and describing the effects on gene expression. I will investigate how the local chromatin environment is influenced by changes in DNA methylation using ChIP-seq to histone and TET proteins. I further aim to explore whether changes in methylation are detectable at the single cell level. By developing a comprehensive panel of inflammation sensitive methylation sites I will explore whether these changes can be observed in clinical samples from cancer and infection, furthering our understanding of how past inflammatory events modify future responses.

Amount: £1,068,876
Funder: The Wellcome Trust
Recipient: University of Oxford

The mechanisms and physiology of ER-associated protein degradation 05 Apr 2016

The endoplasmic reticulum (ER) is the largest membrane-bound organelle in cells, playing several essential functions such as the biogenesis of secreted proteins, synthesis of lipids and assembly of the nuclear envelope. A long-term goal of my lab is to dissect how these functions are coordinated and ER homeostasis achieved. Proteolysis through the ER-associated degradation (or ERAD) pathway has emerged as key in maintaining ER homeostasis and will be the focus of this proposal. Studies on ERAD have focused primarily on the role of this pathway in degrading misfolded proteins. More recently, our lab revealed a much wider range of ERAD substrates, including folded ER proteins that are degraded in a regulated, signal-specific manner. These findings show that ERAD also defines the functional ER proteome and is important for lipid homeostasis or establishment of specialized ER subdomains. Moreover they raise several fundamental questions: (1) what are the regulated ERAD substrates under different metabolic states? (2) is regulated ERAD necessary for the transition between those states? (3) what is the mechanistic basis of substrate specificity in regulated ERAD? Addressing these issues will reveal key mechanisms of ER organization and homeostasis, and might provide important insights into common diseases such atherosclerosis and cancer.

Amount: £1,197,978
Funder: The Wellcome Trust
Recipient: University of Oxford

Open access block grant award 30 Sep 2016

Not available

Amount: £85,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Cellular Structural Biology 30 Sep 2016

Oxford - Cellular Structural Biology

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Cellular Structural Biology 30 Sep 2016

Oxford - Cellular Structural Biology

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford