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Results

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

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

Laser capture microdissection to investigate bacterial handling defects in patients with monogenic inflammatory bowel disease 01 Apr 2016

Inflammatory bowel disease (IBD) is linked to defective bacterial handling in Crohn’s disease and monogenic diseases (Hugot et al. Nature 2001, Ogura et al. Nature 2002, Cooney et al. Nature Medicine 2010, Uhlig Gut 2013 and Uhlig et al. Gastroenterology 2014). Hypothesis: If defects in clearance of ingested bacteria cause granuloma formation we expect to find surviving bacteria (and its mRNA) in the granuloma lesions. Experimental Design Formalin-fixed archived tissue sections from patients with monogenic forms of IBD (XIAP , G6PC3 or HPS1) will be cut onto a capture membrane and stained with H&E. Granuloma will be isolated using laser capture micro dissection. 16S rRNA will be amplified using high fidelity PCR and sequenced. Comparison of the obtained sequences with public databases will establish which bacterial taxa. This project will help to identify bacteria that survive within macrophages and improve the understanding of the host-environment relationship.

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

Modelling the evolutionary epidemiology of chronic viral infections: Incorporating host heterogeneity into nested models of virus evolution 01 Apr 2016

One of the principal challenges in epidemiology is using mathematical models to plan disease control. This is made more challenging by pathogen evolution, which increases the complexity of disease dynamics, acting as a barrier to effective control. Chronic viruses such as HIV exhibit evolution over significantly shorter timescales than the long duration of infection. Understanding pathogen evolution and including it in models is therefore a key challenge for mathematical biologists. This project will explore how heterogeneity between hosts affects evolutionary dynamics at the population scale, building on a model in an existing paper that assumes that all hosts are identical. In this project, the model will be extended to include the heterogeneous immune responses to infection observed in different individuals. The dynamics of this new model will then be compared with the model in which all individuals are identical. Mathematical techniques required for this project include analysis of integro-differential equations (such as calculation of equilibria) and examination of the behaviour of integro-differential equations via numerical solution. The key goal is to develop a model of virus evolution that includes heterogeneous host types, and to investigate the evolutionary behaviour predicted by the model with different extents of host heterogeneity.

Amount: £1,750
Funder: The Wellcome Trust
Recipient: University of Oxford

Man and Sun in the Pre-Modern World 25 May 2016

The project 'Man and Sun in the Pre-Modern World' would involve working with the curator of the future temporary exhibition, 'The Sun', at the Science Museum. 'The Sun' is scheduled to take place in spring or autumn 2018, which will be the year that ESA’s Solar Orbiter and NASA’s Solar Probe Plus is launched, and the 150th anniversary of the discovery of helium. My chief involvement would be to enhance the pre-modern component of the exhibition, studying the relationship between human beings and the Sun, and identifying the art and artefacts best suited to tell this story. I would be interested in assisting with the development of the project as it shapes up in the next few months, making use of my experience in project management. In addition, I would like to plan, together with the curator, a 'history of the Sun' book that would be published in conjunction with the exhibition and be written for a non-academic audience. The key goals of my project would be to further my knowledge of organising thematic exhibitions, to improve my public outreach and dissemination skills, and to gain more experience in the holistic treament of complex interdisciplinary subjects such as 'the Sun'.

Amount: £21,802
Funder: The Wellcome Trust
Recipient: University of Oxford

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

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: £14,698,261
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: £11,890,784
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

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

Viet Nam Major Overseas Programme Core Grant Renewal 2010-2015 supplement: Patan Hospital emergency equipment 29 May 2015

Infectious diseases remain a very real global threat. In addition to the endemic infections there has been emergence of new, often zoonotic, diseases and the rise of drug resistance among all major pathogens. Asia is the epicentre of these changes. Within a four hour flight of Vietnam live half the world s human population and 75% of the world s poultry. The region is a global hot spot for the emergence of new infectious diseases, it leads the world in drug resistance, and is going through an unprecedented period of social and environmental change. The future impact of these changes is difficult to predict but it will influence disease patterns both directly and indirectly. We believe that this trusted collaboration between Vietnam and the Wellcome Trust is uniquely placed to address these complex issues both nationally and regionally. Our work keeps health research as the focus with an integrated science programme and a particular interest in the interface between human and animal health. Our training and public engagement programme from schools to post-docs and lay people is helping to build a critical mass of Asian clinicians and scientists dedicated to the development of the region and the health of its people.

Amount: £97,609
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

A spatial data repository for the analysis of insecticide resistance in malaria vectors. 11 Jun 2015

We will build a resource to provide georeferenced data on resistance to multiple classes of insecticide in vectors of malaria worldwide. Our key objectives are i) to collate the largest global repository of field survey data for insecticide susceptibility, ii) to generate predicted values for insecticide susceptibility across locations and times to provide estimates for locations that have no field survey data and to allow users to investigate the spatiotemporal patterns of resistance, and iii) to collate the largest global repository of field survey data for resistance mechanisms. Cutting across all three objectives, our aim is to provide datasets that are formatted for use in mathematical models of malaria transmission and meta-analyses of insecticide resistance. The survey data will be cleaned, standardised, disaggregated and georeferenced before they enter the repository, to ensure users can conduct meta-analyses on data from diverse sources and study designs. We will use geostatis tical techniques to generate posterior distributions of predicted values that can be used by mathematical modellers and we will also provide a mean estimate for each location and time, together with a summary statistic for the uncertainty in each estimate. All data will be released on a free and open access basis.

Amount: £669,719
Funder: The Wellcome Trust
Recipient: University of Oxford

Improving the management and prevention of tetanus in Vietnam. 13 Apr 2015

Key Goal 1. To establish whether intrathecally administered antitoxin reduces the requirement for mechanical ventilation, and in addition reduces mortality, duration and cost of intensive care unit stay, duration of mechanical ventilation, requirement for antibiotics, and incidence of predefined nosocomial infection and autonomic nervous system dysfunction. I will perform a randomised-controlled trial of intrathecally administrated antitoxin in 270 adult patients, allocating patients to intrath ecal administration or sham procedure in addition to standard intramuscular antitoxin and routine care. Key Goal 2. To develop a simple prediction tool that can be applied clinically to allow early diagnosis and intervention in autonomic nervous system dysfunction. I will quantify heart rate variability in 60 patients with tetanus, correlating sequential readings with the development of autonomic nervous system dysfunction and outcome. Key Goal 3: To create an age/sex-stratified model o f population immunity in Vietnam to ascertain whether current booster programmes are adequate and what proportion of adults lack protection from tetanus. I will measure serum anti-tetanus antibody concentrations using enzyme-linked immunosorbent assay (ELISA) in 4000 serum samples from a recently-established serum bank containing samples from multiple sites in Southern Vietnam.

Amount: £569,168
Funder: The Wellcome Trust
Recipient: University of Oxford

WACCBIP-Wellcome Trust DELTAS Programme 05 May 2015

The proposed DELTAS Programme seeks to strengthen and extend the scope of the mission of the West African Centre for Cell Biology of Infectious Pathogens (WACCBIP: www.waccbip.org), which was established at the University of Ghana (UG) in 2013. We believe that the vision of the DELTAS initiative aligns perfectly with our own aspirations at WACCBIP, where our mission is to improve diagnosis, prevention and control of tropical diseases by providing advanced level training and research on the cell and molecular biology of infectious pathogens. WACCBIP faculty are drawn from the Department of Biochemistry, Cell and Molecular Biology (BCMB), and the Noguchi Memorial Institute for Medical Research (NMIMR) at UG as well as seven partnerinstitutions within Africa. International faculty include several leading scientists from UK institutions, and members of the American Society for Cell Biology. WACCBIP was selected by the World Bank as one of the African Centres of Excellence for Higher Education, and received funding to build capacity for training of PhD and Masters students in Biochemistry and Molecular Cell Biology. This application seeks support from the DELTAS scheme for increased impact and long-term sustainability in the following ways: 1. Develop the first graduate and professional Human Genetics programme in Ghana, which will complement our existing pathogen biology research training. This programme will provide a structured research training platform to synergize with existing genetics training programmes led by the H3Africa network. 2. Develop a post-doctoral programme to help keep newly qualified PhDs in Africa and attract African scientists who have completed their PhDs abroad to return home. These postdoctoral fellows will conduct supervised research at WACCBIP and its regional partner institutions. 3. Strengthen our co-supervisor system through a Student Visitor programme, sothat PhD students and postdocs will be funded for six-month visits to the laboratories of cosupervisors in the UK or USA to hone their research skills. 4. Strengthen the mentoring system so each postdoctoral and PhD trainee will have a local mentor and access to advice from a UK or US scientist. 5. Develop a short course in research ethics that will be run annually to train young African scientists on responsible conduct. The goal of the proposed programme is to provide advanced training of health professionals and increase research and innovation to guide development of new approaches to disease diagnosis, prevention, and control. Effective training programs must be anchored by a strong, well-structured, and focused research portfolio. Therefore, this application seeks to build on our strength in pathogen biology research by incorporating a genetics curriculum and research platform, which is critical for a complete understanding of disease mechanisms for both communicable and noncommunicable diseases. Thus, the proposed research training will incorporate genetics into the study of host-pathogen interactions, as well as in investigating the molecularmechanisms that predispose individuals to the development of non-communicable diseases. This application builds a coalition of local, regional and international partners who have advanced resources and expertise in human genetics and pathogen biology research to support the proposed training programmes.

Amount: £132,017
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

Large Scale Biomanufacture of a Monovalent Ebola MVA Vector and Heterologous Boosting of Primed Subjects in Mali and the UK 19 Dec 2014

Conversations between the principal investigator, The Wellcome Trust and various other parties have led to this application being submitted for fast track assessment. The goal is to demonstrate the safety and immunogenicity in UK and West African adults of a vaccine for the Zaire strain of Ebola virus that has shown significant promise in pre-clinical studies conducted at the NIH in collaboration with Okairos, now GSK. Demonstration of the safety and immunogenicity of this vaccine by November 2014 in about 140 subjects would provide WHO with the option of providing this vaccine to affected countries, particularly for use in health care workers, for whom no other intervention is currently available.

Amount: £1,050,000
Funder: The Wellcome Trust
Recipient: University of Oxford

FITNESS: FIt To Study 01 Oct 2014

Not available

Amount: £511,532
Funder: The Wellcome Trust
Recipient: University of Oxford