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Recipients:
University of Oxford
Amounts:
£1,000 - £5,000

Results

Understanding the functional role of GABA across the human motor network 05 Dec 2016

Understanding the functional role of GABA across the human motor network

Amount: £214,011
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural and functional dissection of the RH5:CyRPA:RIPR complex required for erythrocyte invasion by Plasmodium falciparum 05 Dec 2016

Invasion of human erythrocytes by Plasmodium falciparum is essential for parasite replication and occurs before the symptoms of malaria. It is a complex process involving many parasite surface proteins. Recently, one of these, RH5, emerged as the leading vaccine candidate to target the ‘blood stage’ of the parasite life cycle. RH5 interacts with erythrocyte basigin while monoclonal antibodies that prevent binding also prevent erythrocyte invasion. Immunization with RH5 protects animal models from parasite infection and RH5 enters human clinical trials in 2016. We already determined the structure of RH5 bound to basigin and inhibitory antibodies: a major goal of my investigator award. On the merozoite surface, RH5 forms part of a larger complex, interacting with CyRPA, RIPR and a fourth, GPI-anchored component. RH5, CyRPA and RIPR are each essential for erythrocyte invasion and are targets of antibodies that block invasion. Despite this, their functions are unknown, leaving a major gap in our understanding of erythrocyte invasion by Plasmodium falciparum. We will now undertake structure-function studies of the RH5:CyRPA:RIPR complex. Working with Simon Draper, we have developed eukaryotic expression systems to produce RH5, RIPR and CyRPA. We assembled them into a complex and showed that this is elongated, homogeneous and rigid by negative stain electron microscopy. Monoclonal antibodies targeting each component havebeen generated. We will now determine the structure of this recombinant RH5:CyRPA:RIPR complex using electron cryo-microscopy, and investigate where inhibitory monoclonal antibodies bind.

Amount: £150,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Linking human genotype and immunological phenotype to understand pathogenesis and improve treatment in tuberculosis 19 Jun 2017

TB kills more people worldwide than any other infectious disease, yet its pathogenesis is still poorly understood which hinders therapeutic advances. The heterogeneity of immunological responses and clinical presentations make the investigation of the major determinants of outcome challenging. Host genetic variants regulate the immune response during infection, drive immunological pathogenesis of the disease, and can lead to poor outcomes. My aim is to link human genotype and immunological phenotype to better understand TB pathogenesis and thus improve TB treatment. The fellowship has three key goals: Investigate the impact of dexamethasone on transcriptional profiling of the immune response, bacterial clearance and survival/death in TB meningitis Determine whether LTA4H genotype can be used to predict inflammatory transcriptome and to identify additional genes associated with inflammatory transcriptome variation in TB meningitis Link human genotype and transcriptional immune responses associated with treatment failure or relapse in pulmonary TB To pursue these goals, I will use RNA-Seq to provide data on both human variants and whole-genome gene expression. These results will reveal the pathogenesis of different forms of TB, including pulmonary TB, meningeal and multi-drug resistant TB. Pathways associated with inflammasome and neutrophil-driven immunopathogenesis will be a particular focus.

Amount: £824,755
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

Molecular mechanisms of HIV-1 restriction by capsid-sensing host cell proteins 05 Apr 2017

Infections by retroviruses, such as HIV-1, critically depend on the viral capsid. Many host cell defence proteins, including restriction factors Trim5alpha, TrimCyp and MxB, target the viral capsid at the early stages of infection and potently inhibit virus replication. These restriction factors appear to function through a remarkable capsid pattern sensing ability that specifically recognizes the assembled capsid, but not the individual capsid protein. Using an integrative and multidisciplinary approach, I aim to determine the molecular interactions between the viral capsid and host restriction factors, TrimCyp and MxB, that underpin their capsid pattern-sensing capability and ability to inhibit HIV-1 replication. Specifically, I will combine cryoEM and cryoET with all-atom molecular-dynamics simulations to obtain high-resolution structures and atomic models of the capsid and host protein complexes (in vitro), together with mutational and functional analysis as well as correlative light and cryoET imaging of viral infection process (in vivo and in situ), to reveal the essential interfaces in their 3D organization for HIV-1 capsid recognition and inhibition of HIV-1 infection. Information derived from our studies will allow to design more robust therapeutic agents to block HIV-1 replication by strengthening the pattern recognition feature.

Amount: £1,476,229
Funder: The Wellcome Trust
Recipient: University of Oxford

Defining mechanisms of mycobacterial protective immunity using human experimental medicine and murine models 05 Apr 2017

Progress in the development of an effective TB vaccine is hindered by an incomplete understanding of protective immunity, and by a lack of knowledge as to which proteins from Mycobacterium tuberculosis (M.tb) are protective. Most of our understanding has come from studies in mice, and studies using blood from patients with TB. The lung is the primary site of infection in TB. Lung and blood responses may differ, and murine and human responses can also differ. I have developed a safe human infection model in which BCG, a replicating mycobacterial strain, is delivered by aerosol directly to the lungs of healthy volunteers. I will use this model to define the innate and adaptive, systemic and mucosal immune responses, in humans. I will then use an in-vitro mycobacterial growth inhibition assay to assess whether these responses are protective. I will use this information to identify which components of host immunity are important in protection in humans. We will also use state-of-the-art mass spectrometry to identify which M.tb proteins are naturally presented to the human immune system, and determine if these proteins confer protection in a murine M.tb challenge study. This information will facilitate the development of effective vaccines.

Amount: £1,953,582
Funder: The Wellcome Trust
Recipient: University of Oxford

Characterising extreme innate immune response phenotypes informative for disease using a functional genomics approach 30 Nov 2016

The overall aim is to define and characterise extreme innate immune response phenotypes in order to gain insights into the functional alleles driving such differences between individuals; biological consequences in terms of gene regulation, cellular function and disease; and opportunities for therapeutic intervention. Key goals are (1) to analyse existing transcriptomic and expression quantitative trait mapping datasets for primary monocytes activated by lipopolysaccharide (endotoxin) or interferon-gamma from a large cohort of healthy volunteers to identify extreme responders (aggregated and gene level), using genetics to resolve functional alleles then validate and establish functional consequences including through chemical probes; (2) to use genome editing to conduct high-throughput screens in human induced pluripotent stem cell derived monocytes complementing the genetic data; (3) to define key nodal genes and networks for drug target discovery and prioritisation; and (4) to characterise prioritised genes and functional alleles modulating gene transcription and epigenetic regulation relevant to disease. Anticipated outcomes are improved understanding of pathophysiology in immune-mediated disease notably sepsis; exemplars to the field of how to establish mechanism for functional alleles involving regulatory genetic variants; improved interpretation of genome-wide association studies; novel nodal points involving TLR and related pathways as drug targets; and better drug target prioritisation.

Amount: £1,575,666
Funder: The Wellcome Trust
Recipient: University of Oxford

Forecasting dengue cases: Vietnam as a case study 19 Jun 2017

Vector-borne infectious diseases continue to be a burden to Vietnam’s economy and population health. Understanding the spatiotemporal patterns of the disease transmission is thus vital for planning resources and targeting control measures. In this work, we propose a large-scale study on how different factors interact and contribute to the dynamics of dengue in Vietnam. We will employ multiple modelling techniques to analyse the dynamics of the disease and how to best predict future cases. We hypothesise that urbanisation has played a significant role in deriving the distribution of the Aedes mosquito and on dengue transmission, and will therefore incorporate factors about urbanisation gained from satellite images into predictive models. These models will use three main methods: statistical, mechanistic and machine learning. The key goal is to predict the number of new dengue cases as far as possible, and we will work in collaboration with those who use the forecasts to assess the most useful timeframe and accuracy. A particular aim will be the prediction of upcoming hotspots of dengue transmission so that hospitals can plan their resources. We will work to present the results clearly so they can best be used to help to reduce dengue burden in Vietnam.

Amount: £82,952
Funder: The Wellcome Trust
Recipient: University of Oxford

Targeting malaria hotspots in Myanmar: An individual-based modeling approach 22 Nov 2016

The epidemiology of malaria in Myanmar has been changing with its decreasing incidence in Myanmar, while there is also an urgent need to address emerging resistance to artemisinin. Current malaria control strategies are no longer enough to achieve elimination. New strategies, like targeting of malaria hotspots where transmission intensity exceeds the average, have been suggested both by studies and the WHO. Such targeted strategies has been implemented in Kayin, Myanmar. However, detection of hotspots using qPCR has been limited to randomly selected villages because of the financial and operational constraints. This could be optimized by a simulation model. The proposed project will develop an individual-based mathematical model to: - Understand/model the changing epidemiology of malaria as its incidence declines in Myanmar - Derive cost-effective strategy to identify and treat malaria hotspots in Kayin, Myanmar As inputs, the model will have census data, population movement, and malaria data from relevant sources to create a dynamic, synthetic population. Simulated individuals will have their own risk of infection, health behaviour and response to treatment which will influence the overall disease transmission dynamics. A corresponding mosquito model will drive the force of infection for humans. Several detection methods and treatment strategies will be simulated.

Amount: £128,087
Funder: The Wellcome Trust
Recipient: University of Oxford

Future of Animal-sourced Foods (FOAF) 06 Oct 2016

Changes in the amount and type of animal-sourced food (ASF) we consume, and in the way they are produced, are critical drivers of global human health and environmental quality. The project will develop novel policy tools and interventions to allow more informed and effective action to be taken to maximise the health and environmental co-benefits of changes in ASF consumption. We shall build a quantitative food system model incorporating economic, health and environmental modules that will allow the effects of existing drivers and novel policy interventions to be assessed. We shall exploit unique epidemiological resources to provide new evidence about how different types of ASF affect health, and conduct experiments to develop new interventions to influence the consumption of ASFs and ASF substitutes. A social-science component will research how social norms and political economic factors affect the practicality and acceptability of interventions, and how this may be changed. The effects of different types of ASF production on climate change, water use and quality, and ecosystem functions will be measured and brought together for the first time. The project will develop a distinct work stream in China and engagement with multiple audiences will be integral to all its activities.

Amount: £4,391,572
Funder: The Wellcome Trust
Recipient: University of Oxford

Future of Animal-sourced Foods (FOAF) 06 Oct 2016

Changes in the amount and type of animal-sourced food (ASF) we consume, and in the way they are produced, are critical drivers of global human health and environmental quality. The project will develop novel policy tools and interventions to allow more informed and effective action to be taken to maximise the health and environmental co-benefits of changes in ASF consumption. We shall build a quantitative food system model incorporating economic, health and environmental modules that will allow the effects of existing drivers and novel policy interventions to be assessed. We shall exploit unique epidemiological resources to provide new evidence about how different types of ASF affect health, and conduct experiments to develop new interventions to influence the consumption of ASFs and ASF substitutes. A social-science component will research how social norms and political economic factors affect the practicality and acceptability of interventions, and how this may be changed. The effects of different types of ASF production on climate change, water use and quality, and ecosystem functions will be measured and brought together for the first time. The project will develop a distinct work stream in China and engagement with multiple audiences will be integral to all its activities.

Amount: £947,700
Funder: The Wellcome Trust
Recipient: University of Oxford

Chromosome and Developmental Biology. 30 Sep 2017

Not available

Amount: £2,720,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Genomic medicine and statistics 30 Sep 2017

Not available

Amount: £2,580,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Neuroscience 30 Sep 2017

Not available

Amount: £2,980,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Cellular Structural Biology 30 Sep 2017

Not available

Amount: £2,460,000
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £2,228,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural studies of bacterial nucleic acid transport proteins 31 Jan 2017

Horizontal gene transfer contributes to genetic plasticity in bacteria and is of great clinical relevance as it contributes to the spread of antibiotic resistance genes. One mechanism of horizontal gene transfer in bacteria is transformation. While the phenomenon of transformation has been known for many decades, little is known about the mechanistic steps of exogenous DNA uptake into bacterial cells. The most obvious problem is how the DNA gets past the cell envelopes. ComEC is believed to be the protein that forms an aqueous pore that allows transport of DNA into the cytoplasm through the bacterial plasma membrane. The protein represents a novel transport protein, and no structural and very little functional information is available. The aim of the project is to structurally and functionally characterize ComEC proteins using modern protein expression and screening techniques, advanced structural approaches (X-ray crystallography, cryo-electron microscopy) and functional studies (fluorescence microscopy, biophysics), in order to build a model for DNA transport across the plasma membrane into the cytoplasm.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Structure of the Type Three Secretion System Export Gate 31 Jan 2017

I will study the mechanism of protein export in the injectisome by elucidating the structure of one of its central components, the export gate. The injectisome is a large, molecular nanomachine which injects effector proteins into cells of the hosts of many bacterial pathogens. The export gate is the protein channel at the heart of this syringe-like type three secretion system (T3SS), and the structure of this channel will provide important insight into how it may function: For example, the complex may be actively involved in guiding substrates across the inner membrane or merely provide a passive conduit for unfolded proteins. In addition, there is the question of how such a complex may be "plugged" during periods of inactivity. I have recombinantly produced the export gate complex from the injectisome and also from the flagellum which possesses a related T3SS (rotation reports), and the tools of structural biology will continue to be used on them. Furthermore, I will purify larger complexes, consisting of the export gate and other T3SS proteins. This will enable me to study the structure and interactions between the gate and subunits such as the substrate specificity switch.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford