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Recipients:
University of Oxford
Award Year:
2016

Results

The role of BMP signalling in diseases of the motor unit 06 Dec 2016

<p>Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset, neuromuscular disease characterized by lower motor neuron degeneration as result of misfolding and accumulation of mutant Androgen Receptor (AR). In recent years this scenario of selective neuronal vulnerability has been challenged by the discovery that in SBMA, as in other diseases of the motor unit, skeletal muscle, rather than being a mere bystander of motor neuron degeneration, is primarily affected and therapies exclusively targeting muscle ameliorate the pathology in motor neuron while preventing the development of a neuromuscular phenotype in animal models. My goal is to elucidate the molecular mechanisms underlying the intrinsic contribution of skeletal muscle in SBMA pathogenesis. I will investigate the role of the Bone Morphogenetic Protein (BMP) signalling pathway in SBMA pathophysiology, testing the central hypothesis that failure to activate the protective BMP pathway in SBMA muscle in response to denervation causes primary muscle atrophy and affects motor neuron ability to cope with the stress posed by mutant AR. The rationale is to provide a molecular basis for the cell-autonomous and non-cell autonomous roles of muscle in the mechanisms of toxicity in SBMA and other diseases of the motor unit and to identify novel therapeutic targets.</p>

Amount: £1,048,938
Funder: The Wellcome Trust
Recipient: University of Oxford

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

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

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

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

<p>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 &lt;50% of patients. Furthermore, Southeast Asia is highly susceptible to the emergence of novel and drug resistant pathogens. New diagnostic techniques are urgently required for rapid response to future outbreaks, and to improve patient outcomes.</p> <p>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:</p> <ol> <li>To determine whether Mass spectrometry of cerebrospinal fluid (CSF) will identify protein/peptide signatures associated with different infectious aetiologies.</li> <li>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.</li> <li>To determine whether NGS can provide rapid, whole genome sequence-based prediction of antimicrobial susceptibility for <em>Mycobacterium tuberculosis</em> and <em>Streptococcus pneumoniae</em>. &nbsp;</li> </ol> <p>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.</p>

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

Dissecting the antibody response to Plasmodium falciparum-infected erythrocytes 09 Nov 2016

<p>The antibody response against <em>Plasmodium falciparum</em>-infected erythrocytes (IEs) has been associated with protection against malaria, but the characteristics of this response at the monoclonal antibody level remain an open question. We have recently developed a high-throughput platform to isolate monoclonal antibodies against IEs that allowed us to identify novel LAIR1-containing antibodies that target RIFINs on the IE surface (Tan et al. 2016, <em>Nature</em>). Here, we propose to use this technology to interrogate the immune response of well-characterized malaria-exposed Malian individuals against IEs at the monoclonal antibody level. We plan to: a) compare the responses of naturally protected and non-protected individuals to identify potential signatures of protection, b) isolate antibodies that broadly target late-stage IEs and identify novel conserved antigens as malaria vaccine candidates, and c) study the repertoire of LAIR1-containing antibodies in Malian individuals. We believe that this plan is feasible, as we have obtained preliminary data suggesting that several Malian plasma recognize the majority of late-stage IEs and that a sizable proportion (5-10%) of these individuals possess LAIR1-containing antibodies. From this work, we hope to identify aspects of the antibody response that protect malaria-exposed individuals, potentially including broadly reactive antibodies against conserved IE antigens.</p>

Amount: £250,000
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

<p>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.&nbsp;In short, we will systematically characterise the receptor mechanisms that mediate the effect of short-wavelength light on circadian regulation in humans.</p>

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

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

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

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

Open access block grant award 30 Sep 2016

Not available

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

Open access block grant award 30 Sep 2016

Not available

Amount: £75,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Open access block grant award 30 Sep 2016

Not available

Amount: £130,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Open access block grant 2016/17 30 Sep 2016

Not available

Amount: £1,137,787
Funder: The Wellcome Trust
Recipient: University of Oxford

Targetting optogenetic constructs to retinal ON-Bipolar cells 30 Sep 2016

<p><em>&rdquo;How best can optogenetic constructs be targeted to retinal ON-Bipolar cells to restore functional vision?&rdquo;</em></p> <p>This project aims to use the human photopigment melanopsin to induce light responses in retinal ON-bipolar cells (optogenetics) of a mouse model, blind from retinal degeneration, in order to restore functional vision. This comprises three key goals:</p> <p>&nbsp;</p> <p>&nbsp;<u>Goal 1 &ldquo;When&rdquo;</u></p> <p>To further describe changes in bipolar cells over time during retinal degeneration in terms of their gene expression and association with other cells in the mouse model.</p> <p><u>Goal 2 &ldquo;What&rdquo;</u></p> <p>To determine if melanopsin - or an alternative construct (Channel Rhodopsin - ChR2) - is more efficacious in restoring functional vision. Quantified:-</p> <ul> <li>At a cellular level (Calcium imaging, Electrophysiology)</li> <li>At an organism level (Behavioural paradigms)</li> </ul> <p><u>Goal 3 &ldquo;Where&rdquo;</u></p> <p>To determine if bipolar cells &ndash; or an alternative target (retinal ganglion cells) - are more efficacious in restoring functional vision by melanopsin expression (quantified as in goal 2).</p> <p>&nbsp;</p> <p>The eventual purpose of these goals is, along with parallel work, to develop an application to the Gene Therapy Advisory Committee (GTAC) to conduct a clinical trial to restore <em>functional</em> vision in patients blind from inherited retinal degenerations.</p>

Amount: £285,040
Funder: The Wellcome Trust
Recipient: University of Oxford

The Role of the Adaptor Protein-2 Sigma Subunit (AP2σ) in Calcium Homeostasis 30 Sep 2016

<p>G-protein coupled receptors (GPCRs) facilitate cellular responses to extracellular stimuli, and GPCR mutations result in many diseases, including endocrine disorders. Mutations of the calcium-sensing receptor (CaSR), a pivotal GPCR in calcium homeostasis, resulting in loss-of-function or gain-of-function cause familial hypocalciuric hypercalcaemia type-1 (FHH1) and autosomal dominant hypocalcaemia type-1 (ADH1), respectively. FHH and ADH are genetically heterogeneous, and loss-of-function or gain-of-function mutations of the G-protein-&alpha;<sub>11 </sub>utilised by CaSR, cause FHH2 and ADH2, respectively; while loss-of-function mutations of adaptor protein-2 sigma subunit (AP2&sigma;), which is critical for clathrin-mediated endocytosis, cause FHH3. To date, the reported AP2&sigma; mutations, which cause only FHH3 but not ADH, all affect residue Arg15 and impair CaSR signalling and trafficking. However, the Thakker group have recently identified seven other AP2&sigma; variants (Arg3His, Ala44Thr, Phe52Tyr, Arg61His, Thr112Met, Met117Ile, Glu120Gly), and my goal is to determine the roles of these AP2&sigma; variants in calcium homeostasis by:&nbsp;</p> <p>1) Characterising their structural-functional relationships by <em>in vitro</em> studies that assess effects on three-dimensional models and on CaSR signalling and trafficking pathways.&nbsp;</p> <p>2) Determining <em>in vivo</em> phenotypes of AP2&sigma; mutations by generating knock-in mouse models, using CRISPR-Cas.&nbsp;</p> <p>3) Assessing pharmacological effects of drugs, e.g. velcalcetide, using above AP2&sigma; <em>in vitro </em>and <em>in vivo</em> models. &nbsp;</p>

Amount: £348,449
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

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

<p>Understanding the functional role of GABA across the human motor network</p>

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

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

<p>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.&nbsp; Although ZIKV is reported to be endemic in Asia its prevalence and true significance in South East Asia is not well characterised.&nbsp; 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).&nbsp; 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.&nbsp; 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 na&iuml;ve populations.</p>

Amount: £20,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - OXION 30 Sep 2016

Not available

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

Oxford - Neuroscience 30 Sep 2016

Not available

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

Oxford - Genomic Medicine and Statistics 30 Sep 2016

<p>Oxford - Genomic Medicine and Statistics</p>

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

Oxford - Neuroscience 30 Sep 2016

Not available

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

Oxford - Immunology, Infection and Translational Medicine 30 Sep 2016

<p>Oxford - Immunology, Infection and Translational Medicine</p>

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