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Award Year:
2016
Recipients:
University of Oxford

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

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

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

The fate of multidrug tolerant bacteria: from single cells to microbial communities. 09 Nov 2016

Many bacterial infections cannot be cured, even when caused by a pathogen that is not resistant to antibiotics. Central to this effect is the presence of a subpopulation of phenotypic variants called persisters, which enter a dormant state and can survive exposure to a broad range of antibiotics, causing recurrent and chronic infections. Persistence can be triggered by a variety of mechanisms, but it is unknown if these different mechanisms lead to the same cell state, and the same tolerance to antibiotics. Because persister cells are rare they are difficult to study with bulk assays. I will use microfluidics and quantitative fluorescence microscopy of Escherichia coli cells to investigate how persistence states differ from one another in their gene expression and their tolerance to antibiotics. I will study how these cells revive from their dormant state, and at what point they become susceptible again. Chronic infections are often associated with biofilm formation, and increased antibiotic tolerance. By imaging persisters within bacterial colonies, I will establish if biofilms directly afford protection against antibiotic treatment, or rather if biofilms simply prevent removal of existing persister cells, allowing them to repopulate after antibiotic treatment finishes.

Amount: £250,000
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

Towards the development of a healthcare ethics of austerity: Frontline healthcare professionals’ experiences of austerity-driven policies in the UK 10 Mar 2016

The 2008 global financial crisis severely affected most European countries. In 2010, the UK government began a self-imposed austerity programme to reduce its budget deficit. Since this time, a growing body of literature has demonstrated the socio-economic consequences of austerity-driven policies and their impact on healthcare provision. However, there has been scarce attention given to generating empirical accounts of the ethical implications of austerity-driven policies on everyday practices, and for frontline healthcare professionals. In addressing these gaps in the literature, this project will not only provide an understanding of how austerity-driven policies and subsequent system reforms impact and shape ideas and healthcare practices of ethical professional conduct but also allow for frontline experiences of those implementing these policies to be captured. This project will adopt an inter-disciplinary approach drawing on methodological and theoretical strengths of sociology and philosophy to answer the question: In what ways have austerity measures and reforms affected the everyday ethical decision-making and experiences of frontline healthcare professionals in NHS? The aims are to: (i) describe frontline healthcare professionals’ experience caring for patients in conditions of austerity, and (ii) examine, through philosophical analysis, the perspectives and ethical issues experienced by frontline healthcare professionals.

Amount: £47,179
Funder: The Wellcome Trust
Recipient: University of Oxford

The mechanisms underlying sensory dysfunction in human pain channelopathies 05 Jul 2016

Neuropathic pain is a major cause of disability affecting 6% of the population and current treatments are inadequate. Aberrant sensory neuronal excitability due to altered ion channel expression and function is fundamental in the development of neuropathic pain. It is increasingly recognised that inherited ion channel variants can have a major impact on sensory function in humans: In Mendelian pain disorders distinct ion channel mutations are associated with both insensitivity to pain and enhanced pain states. Ion channel variants may also modulate the risk and severity of common acquired neuropathic pain syndromes. These ‘pain channelopathies' are not only relevant to clinical diagnostics but also provide fundamental insight into the normal and pathological function of sensory neurons. The aim of this project is to better understand the mechanistic link between ion channel variants and clinical pain states. In this work programme the starting point will be detailed clinical and electrophysiological phenotyping of patients with inherited channelopathies. Novel cellular and animal models will be used to understand how ion channel variants result in aberrant excitability and altered sensory function. Validation of such models would then allow them to be used as a platform to screen analgesic treatments targeting these ion channels.

Amount: £1,533,067
Funder: The Wellcome Trust
Recipient: University of Oxford

Compartmentalisation via liquid-liquid phase separation in cells 01 Jun 2016

Cells spatially and temporally isolate molecules in subcellular compartments to both facilitate and regulate their interactions. In addition to organelles formed by membrane-encapsulation, cells possess membraneless organelles such as nucleoli, Cajal bodies, stress-granules and nuage. These bodies are highly dynamic, and rapidly assemble and dissolve following changes in the cellular environment and cell cycle. They are predominantly associated with nucleic acid biochemistry, and have been linked with neurodegenerative diseases and viral infection. Membraneless compartments typically display the properties of liquid droplets, and form by phase separation of disordered and multivalent proteins, making them exceedingly difficult to isolate and study. By reconstituting model membraneless organelles in cells and in vitro, I have taken significant steps towards characterising their properties. My research shows that their interior solvent environment is distinct from the bulk water in the cell, capable of localizing proteins and nucleic acids, and modulating their structure. However, the biochemical consequences of performing reactions in such environments are unexplored. I propose to use an interdisciplinary approach to explain how liquid-liquid phase separation provides a general organizing principle in cells, and study how the internal organelle environment influences biochemical reactions performed by helicase, nuclease and polymerase enzymes.

Amount: £1,152,782
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural cell biology of bacterial biofilm formation 01 Jun 2016

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

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

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

Functions of the polyamine synthesis pathway in T cell biology 19 Apr 2016

Metabolism is essential for T cell fate and function. This proposal aims to investigate the role of an overlooked aspect of T cell metabolism, the polyamine synthesis pathway. The importance of polyamine metabolism in T cell proliferation, differentiation and function will be characterised using a conditional T cell murine knockout of the master regulator of polyamine synthesis (ODCflox/flox CD4-Cre). Where the polyamine pathway sits in the T cell metabolic network will be investigated in wildtype and ODC-/- T cells using various metabolomic techniques such as Seahorse, proteomics, and analysis of metabolite uptake/usage. How T cells utilise polyamines to drive cell division and differentiation will centre on the ability of polyamines to directly mediate epigenetic modifications and indirectly influence translation through the polyamine-dependent translation elongation factor eIF5a. Analysis of global acetylation/methylation patterns and gene expression in wildtype and ODC-/- T cells will provide insight as to how polyamines influence gene expression relevant to proliferation and differentiation. Similarly, how these molecules influence the translation of proteins also important for cell division and fate will be investigated through proteomic approaches and analysis of translation in ODC-/- and DOHH-/- (an enzyme required for eIF5a activation) T cells.

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

Ethics and Politics of Community Engagement in Global Health Research 29 Feb 2016

This application is for a workshop to be held in Oxford in April 2016 entitled Ethics and Politics of Community Engagement in Global Health Research. The aim of the workshop is to further critical thinking on ‘engagement’ through three modalities. First, the workshop aims to foster knowledge exchange between divergent actors working in and on community engagement ranging from community and institution based engagement practitioners and applied researchers to critical scholars in philosophy, anthropology, sociology, science and technology studies, development studies and political science. Through this exchange, the workshop will address practical and political challenges of ‘engagement’ implementation, and will contribute to conceptual and normative development of these issues. Second, the workshop will further the field by assisting scholars and practitioners to share experiences and challenges of engagement with broader audiences. Pre-circulated papers will be discussed and a selection of these papers included in an edited volume entitled Critical Issues in Community Engagement. Finally, the workshop aims to explore possibilities for a collaborative, comparative research project that moves beyond local specificities to think more broadly about the social and political dynamics of engagement in global health research.

Amount: £9,950
Funder: The Wellcome Trust
Recipient: University of Oxford

China Kadoorie Biobank (CKB) prospective study of 0.5 million adults 16 Jun 2016

CKB is a blood-based prospective study of 512,000 adults, recruited during 2004-8 from 10 diverse regions of China, with extensive data collected at baseline and subsequent resurveys using questionnaires, physical measurements, and stored biological samples. By 1.1.2014, 25,000 deaths and ~1.5M coded disease events had been recorded among participants, through linkages with death and disease registries and national health insurance systems. Genome-wide data are being generated (first phase: ~100,000 participants by Q3/2016), along with blood biochemistry and multi-omics data for nested case-control studies of specific diseases. We are seeking renewal of two-year funding to support core activities to maintain, enhance and share the resource through: (i) continued follow-up of cause-specific morbidity and mortality and hospital records through electronic linkage to health insurance systems; (ii) validation, clinical adjudication and detailed sub-phenotyping for selected diseases (e.g. stroke, IHD, cancer); (iii) maintenance and management of extensive and uniquely large and complex datasets; (iv) enhancement of collaboration and data sharing with the wider scientific community; and (v) maintenance and development of administrative and technological systems underpinning the infrastructure, sample storage and resurvey. The CKB resource will improve our understanding of disease aetiology, risk prediction and development of new therapies, and should benefit populations worldwide.

Amount: £1,737,405
Funder: The Wellcome Trust
Recipient: University of Oxford

Establishing a feeder EM facility for South Parks Road Oxford 05 Apr 2016

In the last two years a convergence of a new generation of cryo-electron microscopes, with the first generation of direct electron detectors, and new algorithms for image analysis have enabled the routine determination of the structure of macromolecular complexes by EM. It is now possible to look directly at molecules as small as 150-200 kDa with an electron microscope and determine their atomic resolution structure; even more revolutionary, tomographic methods allow direct imaging of the internal machinery of cells at the level of single molecules. These advances are bridging the resolution gap between light microscopy and molecular structures. The goal of this proposal is to make our own research part of this revolution. We request funds to purchase two cryo-EM that will allow the collaborative group immediately to accelerate their own research and to nucleate an advanced cryo-EM facility in the South Parks Road science campus of Oxford University. This facility is also part of an Oxford-wide strategic plan, further integrating structural biology, and ensuring that the co-PIs, and others, can effectively generate the preliminary data needed to justify access to the Titan KRIOS microscopes that are now installed at Harwell as a national facility.

Amount: £2,146,619
Funder: The Wellcome Trust
Recipient: University of Oxford

Burden of Zika virus in different South East Asian populations with febrile illness. 30 Sep 2016

Our planned studies will identify if ZIKV is a current and neglected problem in three SE Asian populations located in Thailand, Vietnam and on the Thailand Myanmar border. Although ZIKV is reported to be endemic in Asia its prevalence and true significance in South East Asia is not well characterised. Transmission of ZIKV Myanmar has not yet been reported, there have only been two confirmed cases recently reported in Vietnam and there are only seven published confirmed cases of ZIKV infections in Thai residents (these were reported by the Thai Ministry of Public Health in 2015). There are several cases of confirmed ZIKV infections from travellers returning from Thailand, indicating that ZIKV is an under and/or misdiagnosed infection in this country. Further work is therefore urgently required. This is important not only for local public health planning, but also from a global health perspective as travellers to and from these regions may be at risk of infection with associated complications and/or pose a transmission risk to naïve populations.

Amount: £10,000
Funder: The Wellcome Trust
Recipient: University of Oxford

In vivo investigation of the PARP-1 regulator, HPF1/C4orf27 04 Aug 2016

Poly(ADP-ribosyl)ation is a post-translational protein modification, synthesised by the PARP family of enzymes, that consists of long chains of repeating ADP-ribose nucleotide units. Through the modification of a variety of mediator proteins, PARPs control a number of cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the molecular players involved in these pathways and their mechanism s of regulation remain poorly understood. In recent years, blocking the PARP-regulated pathways using small-molecule inhibitors has become a promising strategy for treatment of cancer and acute cardiovascular conditions. For example, cell-permeable inhibitors targeting the PARP enzymes involved in DNA break repair demonstrated efficacy against certain types of cancer, such as hereditary breast or ovarian cancers. The intriguing alternative approaches to the chemical inhibition of PARPs include t argeting downstream protein effectors of PARP signalling and targeting PARG, the major enzyme that removes poly(ADP-ribosyl)ation. In the proposed studies, we will utilise a combination of biochemistry, cell biology and structural studies to improve our understanding of the function and regulation of PARG enzyme, and also to attempt developing the first specific cell-permeable human PARG inhibitors. Another goal of our studies is to screen for novel PARP-regulated DNA repair factors. Some of the identified proteins will be further characterised to elucidate their exact biochemical functions and regulation in DNA repair. Furthermore, we will explore the potential of these proteins to be exploited as targets for small molecule inhibitor design and cancer therapy.

Amount: £165,310
Funder: The Wellcome Trust
Recipient: University of Oxford

Whole-heart phosphorus spectroscopy at 7 tesla enabled by a whole-body transmit coil 08 Apr 2016

31P magnetic resonance spectroscopy (31P-MRS) has already contributed significantly to our understanding of cardiac metabolism. However, its great promise has so far gone largely untapped because technical limitations require comparatively long acquisitions which have relatively low spatial resolution. The ability to quantify metabolites in each of the 17 cardia segments in under 20 minutes, ideally from a single subject, would represent a step change in the clinical potential of 31P-MRS. To accomplish this, every stage in the protocol for 31P-MRS must be optimised because improvements at each stage are cumulative. Therefore, I propose to address the hardware used for cardiac 31P-MRS, the acquisition pulse sequence, the reconstruction of the acquired data and the post-processing of spectra to estimate metabolite concentrations. The most significant gains are likely to arise by increasing the magnetic field strength from 3T to 7T by employing the UK's first cardiac-capable 7T MRI sc anner, which has just been installed in Oxford, to collect the first cardiac 7T 31P spectra. My proposed visits to leading experts in the USA will build on my existing expertise in 31P-MRS and cardiac 7T magnetic resonance, positioning me well to be at the forefront of future developments in this field.

Amount: £200,000
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

Identification of T-cell epitopes for vaccine targets against melioidosis in North East Thailand. 30 Sep 2016

A greater understanding of immunity to infectious diseases is desirable to improve treatments and vaccine design, especially for intra-cellular organisms which are harder to prevent and cure. One such organism is Burkholderia pseudomallei, a Gram negative bacterium which causes melioidosis in humans which carries a high mortality. The goal of this study is to demonstrate the CD8 response in patients acutely unwell with melioidosis and define key epitopes for vaccine design. 280 patients with ac ute melioidosis in North East Thailand will be studied, both with and without diabetes mellitus. Peripheral blood mononuclear cells will be isolated locally and used to evaluate T-cell responses by ex vivo IFN-gamma ELISPOT and flow cytometry to a panel of candidate proteins and peptides from B.pseudomallei. Cells from people with diabetes in the region and from unexposed healthy control subjects will be used as controls. Information from HLA typing and from the current consortium at the Immune Epitope Database will be used to identify candidate proteins and peptides, and responses to 9-mer peptides will be studied. Other studies of neutrophil function and acute phase response will be studied in parallel to produce a unified dataset covering several aspects of innate and adaptive immune responses.

Amount: £241,835
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