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Recipients:
University of Oxford

Results

Structural characterisation of nutrient and innate immunity factor uptake by trypanosomes. 30 Aug 2013

Human African Trypanosomiasis is caused by the protozoan parasite Trypanosoma brucei, and is fatal if left untreated. Each trypanosome is surrounded by a surface coat of 10^8 variable surface glycoproteins (VSGs), which protect against complement-mediated lysis,and the switching of VSG expression allows evasion of the adaptive immune system. Thisproject aims to understand how the trypanosome takes up both nutrients and human immune factors in the context of the VSG coat. The project will focus on the haptoglobin-hemoglobin receptor (HpHbR), and the transferrin receptor, which allow the parasite to scavenge heme and iron respectively, in complex with human ligands. HpHbR is also involved in uptake of trypanolytic factor 1 (TLF1), a human lipoprotein particle that protects the host from numerous trypanosome species.

Amount: £160,309
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural Biology 30 Aug 2013

Not available

Amount: £160,309
Funder: The Wellcome Trust
Recipient: University of Oxford

Integration of epidemiological and genetic data to reconstruct disease outbreaks in host-viral systems. 24 Jun 2013

The recent history of a virus epidemic can be more accurately reconstructed when genetic and epidemiological data are integrated, compared to focusing on either data type alone. However, current reconstructive approaches are limited, being designed for outbreaks where most cases are identified. We lack a framework capable of powerful inference when more detailed epidemiological and viral genetic data are available, but when a smaller proportion of cases is sampled. I intend to resolve this by developing general Bayesian statistical methods and applying them to host-virus systems for which both viral genetic and host behavioural data are available: hepatitis C virus (HCV) in humans, and influenza in wild birds.Accessing data obtained from collaborators from four cohorts of HCV patients, I will apply improved methods to determine factors associated with increased risk of transmitting HCV. In tandem, I will study longitudinal viral genetic diversity in a resident mute swan colony (Abbotsbury, Dorset). This will test hypotheses that influenza dynamics in long-lived birds are unlike that in the short-lived species on which almost all research focuses. Combining epidemiological and genetic sequence data will increase understanding of the dynamic behaviour of these viruses, which can be translated to improving control and surveillance measures.

Amount: £160,309
Funder: The Wellcome Trust
Recipient: University of Oxford

Monitoring and controlling ion dynamics in parvalbumin-expressing interneuronsduring epileptiform activity. 24 Jun 2013

The disrupted interplay between excitation and inhibition within neuronal networks has long been implicated in seizure pathophysiology. Pharmacological blockade of synaptic inhibition promotes epileptic activity and when inhibitory restraint upon network activity fails, spatially clustered excitatory pyramidal neurons are recruited to epileptiform events. A key challenge is to understand how different populations of inhibitory interneurons contribute to these processes. Recent research has suggested thatparvalbumin expressing (PV+) interneurons play a central role in setting inhibitory restraint within neuronal networks, but the underlying mechanisms remain poorly understood and how the different properties of interneuron populations influence seizure dynamics is not clear. The efficacy of synaptic inhibition is determined partly by the regulation of intracellular chloride levels, as well as how inhibitory interneurons are recruited and their activity is maintained. This project focuses on the role of PV+ interneurons in these processes. The goals are to investigate activity-dependent changes in intracellular chloride levels in PV+ interneurons and to examine the cellular mechanisms that limit inhibitory restraint provided by PV+ interneurons. Thesequestions will be addressed using in vitro and in vivo animal models of focal epilepsy.

Amount: £160,309
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigating the role of KDM2A in CpG island function and transcription regulation. 24 Jun 2013

KDM2A is recruited to CpG islands (CGIs) throughout the genome. CGIs are regions of non-methylated DNA, and are associated with the majority of mammalian gene promoters. Here it has been proposed that KDM2A catalyses the removal of dimethyl histone H3 lysine 36, an abundant modification that can inhibit transcription initiation. Localised removal of this inhibitory mark byKDM2A may contribute to the generation of a promoter-associated transcriptionally permissive chromatin landscape. I aim to directly examine the role that KDM2A plays in regulating CpG island associated chromatin architecture and gene expression. To achieve this, initially a simple transgene reporter system will be used to determine the effect that KDM2A recruitment has on gene expression and to determine which regions of the protein to contribute this activity. Transcription regulation by KDM2A will next be investigated genome-wide, using KDM2A knockout mouse embryonic stem cells. Transcription and chromatin architecture in the wild-type and KDM2A knockout cells will then be examined in detail. This will

Amount: £160,309
Funder: The Wellcome Trust
Recipient: University of Oxford

Control of intestinal immunity by the autophagy protein ATG16L1 18 Jan 2013

Autophagy is a process of recycling intracellular components in response to starvation or stress. It is also involved in clearance of defective organelles, intracellular pathogens and protein aggregates. Polymorphisms in autophagy genes were recently associated with susceptibility to inflammatory bowel disease (IBD); however the mechanisms responsible for this correlation remain unclear. Clinical and experimental evidence suggests that autophagy maycontribute to intestinal homeostasis in several ways, through distinct effects in intestinalepithelial cells and haematopoietic cells. The aim of this project is to test the hypothesis that autophagy contributes to intestinal homeostasis by influencing antigen presentation and inhibiting excessive proinflammatory responses in haematopoietic cells. Therefore, mice will be generated in which the autophagy pathway is selectively ablated in distinct haematopoietic cell lineages. Several complementary models of IBD will be employed to elucidate the functional consequences of autophagy defects in the context of intestinal inflammation. In parallel, in vitro approaches will be applied to characterize the impact of impaired autophagy on cellular physiology, bacterial handling and inflammatory responses in haematopoietic cells. Together, these experiments should identify mechanisms through which the autophagy pathway intersects withother immune pathways in the gut to regulate tissue protective and inflammatory responses.

Amount: £49,941
Funder: The Wellcome Trust
Recipient: University of Oxford

Establishment of a transgenic zebrafish model to study the innate immune response to melanoma 18 Jan 2013

Although immune mechanisms, such as cytokines produced by immune cells in response to the tumour environment, may provide protection against cancer by elimination of transformed cells, they may also aid tumour development by immunosuppressive mechanisms. Epigenetic mechanisms that alter chromatin landscape, enabling the unwrapping of transcriptional programs play important roles in all cellular processes including immune response mechanisms and carcinogenesis. It remains difficult to assess the overall effect of innate immunity during early tumourigenesis since direct in vivo models for evaluating the effects ofthese phenomena on initial tumour growth are missing. We propose to develop a melanoma model in zebrafish to study the initial host immune response to melanoma with particular focus on epigenetic changes. Key Goals 3.1 Establish a zebrafish model system to study the innate immune response to melanoma. 3.2 Characterise the interaction of neutrophils and macrophages with oncogenicmelanocytes as compared to normal melanocytes in vivo. 3.3 Carry out a genome-wide analysis of macrophages and neutrophils' response to melanoma compared to control melanocytes. i. Identify differentially expressed genes by comparing transcriptomes of innate immune cells ii. Identify changes at the epigenomic level in innate immune cells that may be resulting in differential cytokine expression 3.4 Investigate findings in melanoma patients.

Amount: £23,400
Funder: The Wellcome Trust
Recipient: University of Oxford

Fronto-temporal-dopaminergic networks in credit assignment and generalisation 25 Mar 2013

The ability to use prior experience to aid processing when exposed to novel stimuli is vital for decision-making, and is an integral part of a number of models of learning. The aim of the proposed project is i) to elucidate the processes that allow generalisation from one set of circumstances to another, and ii) to establish the role of frontal and temporal lobe circuitry involved in this process, specifically in relation to fronto-temporal interactions and dopamine signalling. This will be achieved by conducting in vivo behavioural research in animal subjects, in conjunction with a variety of neural interference and imaging techniques. It is hypothesised that interactions between orbitofrontal cortex and the temporal lobe may be necessary for learning which elements of a stimulus most reliably signal the presence of reward, and subsequently generalising this information to novel contexts and stimuli. Further, this information should be reflected in phasicdopamine-encoded prediction errors within interconnected parts of the ventral striatum

Amount: £93,005
Funder: The Wellcome Trust
Recipient: University of Oxford

Characterising and targeting the IL-17/IL-23 inflammatory axis in ankylosing spondylitis and inflammatory bowel disease 24 Jun 2013

Compelling evidence implicates the IL-17/IL-23 inflammatory axis in ankylosing spondylitis (AS),rheumatoid arthritis (RA), as well as inflammatory bowel disease (IBD), with early clinical trials targeting this pathway in AS showing promising results. Central to this axis are innate and adaptive immune cells expressing the ROR-gammat transcription factor. Murine studies suggest that small molecules can directly inhibit ROR-gammat. However, It remains unclear which subset of patients or which diseases may be most responsive to blockade of this pathway, or which components of the axis are most critical. Firstly, I will characterize the IL-17/IL-23 axis in the blood and tissue of patients with AS and RA and compare these responses in collaboration with colleagues looking at IBD. Secondly I will compare the effects of ROR-gammat inhibitors with neutralizing antibodies on different classes of ROR- gammat-expressing cells including CD4+, CD8+, CD4-CD8-CD3+ and innate lymphoid cells. The key goals are to identify: 1) The cellular components of this inflammatory axis in the disease setting 2) The effects of inhibitors on the different cell types involved 3) Potential biomarkers for targeting therapy These studies would form the foundation for proof of concept clinical trials with therapeutic implications across the spectrum of inflammatory diseases.

Amount: £233,952
Funder: The Wellcome Trust
Recipient: University of Oxford

Translation of the immunological synapse. 26 Nov 2012

My goal is to further develop the quantitative analysis of the immunological synapse as a diagnostic tool for human translational research and a platform for evaluation of future therapeutics. In order to achieve these goals as soon as possible, we need to scale up and integrate the platform we have developed into the kind of framework that the Structural Genomics Consortium (SGC) has applied to crystallography. In order to achieve this I will use the move to dramatically change the compositio n of my lab from primarily biologists to a mixture of biologists, engineers, mathematicians and medical scientists. Most of the effort will go into developing high throughput immunological synapse analysis and integration of this analysis with study of disease mechanisms and interventions. Like many systems biology efforts we will deliver a large amount of data that will be made publically available through databases and the institute web site. We will develop the standards for sharing image d ata with other labs performing such screens internationally to achieve maximal compatibility. I will link our immunological synapse analysis to genomic and proteomic projects underway at the Oxford Campus to maximize synergy. I will recruit strong interdisciplinary staff and trainees to work at the interface between immunology, structural biology, computer science and engineering. The lab will continue to operate as a training center and will develop new technologies that will complement othe r modes of analysis. The platform will be applicable to reconstitution of other types of cell-cell communication leading to other collaborations.

Amount: £4,871,200
Funder: The Wellcome Trust
Recipient: University of Oxford

Statistical methods for the analysis of genome-wide association and re-sequencing studies. 25 Mar 2013

The primary aim of this proposal is to develop novel statistical methodology for the analysis of next-generation genome-wide association studies (GWAS) of complex human traits. The methodology will consider common and rare genetic variation from diverse ethnic groups assayed through GWAS genotyping arrays and whole-exome or whole-genome re-sequencing. The specific challenge to be addressed in this proposal is to develop methodology to: (i) identify novel loci that contribute to the missing heritability of complex traits by focussing on the analysis of rare genetic variation; and (ii) refine the location of causal variants within established loci through transethnic GWAS meta-analysis. The methodology will be implemented in user-friendly software to be made available to the wider research community, and will be applied to cuttingedge GWAS and re-sequencing studies of a range of complex traits including type 2 diabetes and related metabolic phenotypes. The methodology and analytical results will be disseminated through publications in peer-reviewed journals and presentations at international scientific meetings.The findings of this proposal will contribute to evaluating the utility of next-generation GWAS of common and rare genetic variation for complex trait gene discovery and will provide a more comprehensive view of the genetic architecture of common human diseases.

Amount: £62,500
Funder: The Wellcome Trust
Recipient: University of Oxford

The epidemiology, genomics and longitudinal immune response of Shigella infections in Vietnamese children. 13 Nov 2012

Shigella sonnei is an emergent diarrhoeal pathogen in industrialising countries. Our data from a global S.sonnei collection suggest that this organism is undergoing clonal expansion in Vietnam, influenced by antimicrobial resistance. A lack of a vaccine and a limited understanding of the distribution, incidence and exposure of S.sonnei hinder our ability to control disease and transmission. This project will investigate the genomics, epidemiology, spatial distribution and immune response of S.so nnei infections in Ho Chi Minh City (HCMC). Over 3 years, >5,000 children from HCMC hospitalised with dysentery will be enrolled, providing a longitudinal collection of S.sonnei and metadata. Risk factors and age-specific incidence of S.sonnei will be assessed by performing active diarrhoeal surveillance for two years in a geographically defined community cohort of 1,000 children. The population structure of S.sonnei in HCMC will be defined by genome sequencing >1,000 isolates, providing a compr ehensive understanding of the genetic makeup and the temporal, spatial and phylogenetic relationships of S.sonnei in HCMC. Plasma collected through the hospital and cohort components of this project will be assayed to assess the age-specific seroincidence and the true S.sonnei burden. An antigen array will be developed to assess the natural immunogenicity of novel diagnostics and vaccine candidates.

Amount: £1,569,817
Funder: The Wellcome Trust
Recipient: University of Oxford

Controlling balanced cortical dynamics on slow and fast time scales. 13 Nov 2012

This project studies large neuronal networks that can produce accurate representations of their input, while maintaining the ability to manipulate their internal dynamics, and thus filter out or enhance specific facets of the input. The separation of important and non-important stimuli is essential for all living organisms, but little is known about the synaptic architecture that supports such processing. In the recent past, the balance of excitatory and inhibitory synaptic currents has emerged as a powerful mechanism for signal separation, or gating . In this scheme, an excitatory signal is always delivered in parallel with an inhibitory anti-signal so that the net effect is zero, unless the balance is purposely disturbed to enhance specific signal aspects. Further, inhibitory plasticity has been shown to establish such a balance of excitation and inhibition. Here, I will study how excitatory and inhibitory plasticity can interact to create networks that automatically generate comp lete representations of their input and autonomously enhance important signal facets, a fundamental step towards understanding the functional architecture underlying any thought process. To calibrate our model and confirm its clinical importance, I will collaborate with experimentalists working on similar question in animals, and investigate the neural basis of balanced processing in humans.

Amount: £704,896
Funder: The Wellcome Trust
Recipient: University of Oxford

Deconstructing the molecular basis of cytokine signalling. 05 Jun 2013

How signalling specificity is transmitted by cross-reactive receptors is a fundamental unresolved problem in cell biology. This research proposal aims to elucidate the molecular basis of ligand discrimination by cross-reactive receptors, using shared cytokine receptors as a model system. I plan to take a forward genetic approach, using a non-mammalian cell line, virtually devoid of any ongoing cytokine signalling, to define the relationship between ligands, receptors and active modulators of IL- 2/IL-15 cytokine signalling. Using step-wise reconstitution of signalling components, I will recapitulate cytokine-signalling in insect cells which will allow us to probe if ligand-receptor affinity drives signalling identity. Taking advantage of this reconstitution system I will be able to quantify the proximal signalling induced by a panel of engineered IL-2 and IL-15 cytokines, observe the dynamics of receptor subunits diffusion at the cell membrane and produce a structure of JAK1 bound to th e entire IL-2 receptor complex. This research plan will generate a novel framework for understanding receptor triggering mechanisms and serve as a paradigm for determining the basis of ligand discrimination by cross-reactive receptors. Elucidating receptor signalling mechanisms for key cytokines such as IL-2 and IL-15 could similarly guide development of more precise and effective therapeutic strategies.

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

Sub-millimetre structural connectivity imaging of cortical, subcortical and spinal pathways in humans. 31 Oct 2012

I will enable sub-millimetre diffusion magnetic resonance imaging (dMRI) by developing two techniques designed to take advantage of the benefits of high-field MRI (7 Tesla). First, I will develop the second generation of simultaneous multi-slice imaging for high-field based on my recent PINS radio-frequency (RF) pulse technology[21-23]. Second, I will tailor parallel RF transmission techniques for use with PINS to address critical sources of field inhomogeneity. These advances will enable tr act reconstructions in a number of scenarios that are currently problematic due to fine-scale geometry. In collaboration with Prof. Johansen-Berg, I will validate the high-resolution accuracy to a post-mortem reference resource developed in Oxford by Dr. Miller. I will then address specific challenges that have held back dMRI of the spinal cord during a 12-month placement in Prof. Ladds lab, which has developed spinal imaging hardware and related RF transmit techniques. During the final year, I will return to Oxford to merge these threads of research to produce spinal diffusion techniques for use in pain research, in close collaboration with Prof. Irene Tracey.

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

Returning Genetic Results in Biobanks: Opening an International Dialogue. 30 Aug 2013

We seek funding to support an international Workshop devoted to the issue of return (or feedback) of individual research results and incidental findings in genomic biobanks. Partial funding has been obtained from the Brocher Foundation, U.S. National Institutes of Health, and the Swiss Academy of Medical Sciences. Whether or not to provide research results or incidental findings to participants whose specimens and/or data are collected in biobanks is a matter requiring urgent policy attention. I n 2012, the U.S. NIH established a consortium of funded investigators to address return of results. That mechanism allows for expanded dialogue and collaboration among U.S. researchers, but any national debate is of limited applicability. Comparative work is sorely needed to allow development of sound policy and best practices grounded in a diversity of global perspectives. The Workshop, to be held in November 2013, will bring together experts in the ethical, legal, and social implications (ELSI ) of genetic technologies. The Workshop will explore the issue of feedback of research results broadly, and will also address the cutting-edge issue of return of results to a participants family. This Workshop was enabled by, and will be a proof of principle for the ELSI 2.0 global initiative (Science, 2012).

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

Human mobility in the Indonesian archipelago and risk of malaria importation into the receptive malaria free-zones. 06 Dec 2012

This research will develop the quantitative framework of human mobility and feasibility assessment for malaria elimination in the Indonesian archipelago where the risk of infection with malaria is extremely heterogeneous across the5000 km-long chain of 17,000 islands. Three areas support these central aims: 1) exploration of human movement patterns using the mobile phone data needs tobe conducted to identify movement of infected individuals from high to low transmission areas and movement of susceptible individuals from low to high and back to low transmission areas, 2) malaria imported and outbreak risks will be quantified using derived human movement patterns, risk of infection acquisition and the known parasite rate for each region of their origin, 3) strategic operational feasibility of malaria elimination will be assessed using comprehensive indicators and non-subjective ranking technique to allow objective determination of the elimination feasibility for each district. Critical indicators that constraint districts to achieve their elimination agenda will be identified.

Amount: £249,954
Funder: The Wellcome Trust
Recipient: University of Oxford

International Severe Acute Respiratory Infection Consortium (ISARIC) 30 Nov 2011

It has become increasingly recognized from a series of recent outbreaks of emerging pathogens of global public health importance that mounting clinical research in response toa rapidly emerging infectious disease is extremely challenging, often delayed and of increasing importance. The Consortium will establish a new paradigm for collaborative clinical research in rapidly emerging public health threats with a focus on severe acute respiratory infections. We will do this with the open access development and implementation of inter-pandemic research studies, pre-approval of protocols for future epidemics, and with a new approach to bioethics in emergent events, communication and data and sample sharing. This will be matched by ensuring there is equitable sharing in the benefits of the research. If successful, we hope that this would become an indispensible component of the global research landscape and be a framework for research in rapidly emerging public health threats. The Consortium will be overseen by a Governing Board with an Executive Committee of investigators who will be responsible for the leadership and development of the mission, goals, and objectives of the Consortium. A Secretariat, based in the Nuffield Department of Medicine Oxford University and linking with regional hubs currently proposed for Mexico, Canada, Bangladesh, and Singapore, although others will be added in future, will implement the objectives of the Consortium. We would welcome your advice on membership of the Governing Board, which we propose should be led by an internationally recognized chair and vice-chair from the scientific and/or public health communities and which will bring together global partners interested in changing our research approach to rapidly emerging public health threats.

Amount: £125,000
Funder: The Wellcome Trust
Recipient: University of Oxford

A whole genome association study of major depression 06 Oct 2011

We aim to establish a resource for the identification of susceptibility genes that increase the risk of developing major depression (MD). The aetiology and pathogenesis of MD reflects the joint effects of numerous genetic and environmental risk factors and their interactions, making the detection of individual susceptibility genes extremely difficult, even with large sample sizes. Success will require a coordinated activity, with data being combined from numerous groups across the world. Our p rimary objective is to facilitate this process by establishing a large and freely available data set. We seek support to collect 6,000 cases of recurrent lifetime MD and 6,000 matched controls of Han Chinese ancestry in Shanghai, China, one of the few places in the world where it will be possible to acquire such a sample of high quality phenotypes quickly and inexpensively. We will study only females and will train Chinese doctors in the assessment of cases and in the editing of data to ensure h igh quality data. Cases and controls will be genotyped for a whole genome association analysis will take account of the effects of environmental and other non-genetic risk factors. Genotypes, phenotypes and results will be freely available through a web accessible database.

Amount: £604,800
Funder: The Wellcome Trust
Recipient: University of Oxford