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Recipients:
Broadfield Primary School
University of Oxford
Amounts:
£0 - £500
£500 - £1,000
£50,000 - £100,000
£1,000,000 - £10,000,000
Award Year:
2017

Results

Extension of Serial Femtosecond Crystallography (SFX) at the European X-Ray Free Electron Laser (XFEL) 30 Sep 2017

Third generation synchrotron sources have revolutionised our understanding of the macromolecular machinery of the cell - over 33,000 structures have been elucidated in the last five years, providing atomic detail of macromolecular complexes, membrane proteins and viruses. Fourth generation light sources, such as hard X-ray Free Electron Lasers (XFELs) will allow us to greatly improve one of the bottlenecks of Structural Biology by removing the need for large crystals, which is achieved by outrun ning radiation damage. XFELs also enable sub-picosecond time-resolved analyses and may ultimately provide atomic information for single particles such as viruses and large complexes. The UK is currently not committed to or involved in the construction of a fourth generation light source, including the European XFEL, under construction in Hamburg. This proposal aims to enfranchise the UK structural biology community, amongst the leading in Europe, in this potentially game-changing technology. W e propose to provide training and infrastructure and to directly contribute to the construction and operation of SFX, a user facility for serial femtosecond crystallography at XFEL. An UK Hub at Diamond will allow sample preparation and triage to optimise the use of SFX by UK scientists and maximise the impact of XFEL.

Amount: £692,010
Funder: The Wellcome Trust
Recipient: University of Oxford

DNA origami: how do you fold a genome? 30 Apr 2017

<p>Recent advances in DNA sequencing technology mean that it is now possible to identify genetic variants in patients with specific diseases which either cause or alter their risk of developing that disorder. However, linking these variants to the genes they regulate and the symptoms of the condition itself is time-consuming and challenging. The overarching aim of this project is to develop high-throughout methods to systematically investigate the impact of genetic variants associated with specific diseases on cell function and human health. This will be achieved via collaboration between several groups within the University of Oxford and multidisciplinary external groups, each bringing their own specific field of expertise relevant to the overall aims of the project. Over the past three years, we have developed and refined high-throughput techniques to link genetic variants to the genes they control, and analyse how and why these variants impact the activity of their target gene. Now that we have established these methodologies and associated computational analysis pipelines, we will apply these techniques to variants associated with various conditions during the next two years of the award. In the first instance, these will be disorders associated with red blood&nbsp;cells, multiple sclerosis, and type 2 diabetes. The final stage of the project is to optimize recently developed genome editing techniques to correct any variants that are found to have a functional impact on the condition in question. This will serve two purposes; first it will prove that the variants influence gene regulation and second it will provide the first steps to establishing proof-of principle for gene editing as a potential therapeutic opportunity. Of particular importance to the interpretation of this work will be ongoing basic research in modeling and visualization of how gene activity is regulated in the 3D space of the nucleus, which will aid our understanding of how these specific variants affect the activity of distant genes. Using state of the art methods to visualize and interact with the DNA molecule in three dimensions represents a unique opportunity to intuitively explain these complex but universally important concepts to the public.</p>

Amount: £35,850
Funder: The Wellcome Trust
Recipient: University of Oxford

Enhancing the WT MOP Vietnam's Engagement Programme 30 Aug 2017

<p>In 2015 the WT Major Overseas Programme Vietnam was awarded a renewal of its Core funding. The MOP has a history of successful public engagement, funded through International Engagement awards and from industry sponsorship. However, with the introduction of the Provisions for Public Engagement funding scheme, we applied for funding for engagement at an institutional level, enabling us to create a 5-year strategic plan for developing engagement capacity within the MOP and in the region. Now, 20 months into the award, we reflect on activities to date, and plan strategically for the second part of the programme. The 5-year public engagement programme includes a schools engagement programme (SEP) and a capacity building programme (CBP), both of which have proved to be very successful and highly valued by our local government and school partners. The third focus has been to develop researcher capacity for engagement &ndash; through small grants and offering training and mentoring. We have had a good uptake of these &lsquo;seed awards&rsquo; from MOP researchers and increasing interest in engagement from researchers at local institutes in Vietnam.</p> <p>Schools Engagement: The SEP has been very successful (http://www.mediafire.com/file/td3kaomtu9t7ia7/Application.7z), in particular: afterschool science clubs; weekly science articles in a children&rsquo;s magazine; science theatre; and lab visits enabling young people to interact with scientists. The SEP has also included &lsquo;I&rsquo;m a scientist, Get me out of here&rsquo; - a competition linking children and scientists, run with Gallomanor UK (https://imascientist.org.uk) (https://www.youtube.com/watch?v=n--SJOtFm1w). Capacity building: The CBP was developed in recognition that much of the &lsquo;front-line&rsquo; contact with patients and communities enrolled in clinical trials or cohort studies is from hospital or government study staff. In response we have started a CBP to train and support hospital health care workers (HCMC), community-based data collectors (Nepal) and local vets (in provinces where we conduct research on zoonosis). As the funding for the IAS project and other awards come to an end, we need additional funding to support the current PE team. This application is for additional staff salary costs and to run PE workshops to develop engagement capacity across the region.</p>

Amount: £343,289
Funder: The Wellcome Trust
Recipient: University of Oxford

Public Engagement for the Thailand Major Overseas Programme 2015 – 2020 (supplement) 30 Sep 2017

<p>The Wellcome Trust Thailand Major Overseas Programme&rsquo;s central aim is to improve health and reduce the human disease burden in the developing world. Its strategic objectives are:</p> <ul> <li>The <strong>development of people and institutions</strong>: mentoring world-class clinicians and scientists</li> <li><strong>Disseminating </strong>high-quality research evidence, locally and globally</li> <li><strong>Strengthening governance, management and financial planning</strong>, thus building operational excellence in tackling tropical diseases</li> <li><strong>Public engagement (PE) &amp; outreach</strong>&nbsp;with the communities who host us, in turn inspiring and involving current and future generations in medical research</li> </ul> <p>This application pertains to the last strategic objective of the programme. The &ldquo;must-do&rdquo; engagement activities are part of the Thailand Major Overseas Programme core grant 2015 -2020. In April 2016, the programme received a PPE award (&pound;673,180) &nbsp;to build a core PE team and to pilot some &ldquo;smart-to-do&rdquo; and &ldquo;wise-to-do&rdquo; activities in years 1 and 2 of the core grant and with a view of shaping the PE activities for years 3 to 5. The core PE team is led by Ass. Prof. Phaik Yeong Cheah, who is co-PI on this application.</p> <p>This application is for PE activities in years 3 to 5 based on learnings from our pilot projects and to grow further the PE capacity within the programme.</p>

Amount: £454,843
Funder: The Wellcome Trust
Recipient: University of Oxford

The MYRIAD Project: Exploring Mindfulness and Resilience in Adolescence 30 Jun 2017

<p>The MYRIAD Project: Exploring Mindfulness and Resilience in Adolescence</p>

Amount: £250,800
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

Chromosome and Developmental Biology. 30 Sep 2017

Not available

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

Investigating a role for Z-nucleic acid binding in virus-host interactions 31 Jan 2017

<p>Z-DNA is an alternative conformation of the DNA double helix. The existence of proteins containing Z-DNA binding domains (ZBDs) suggests that nucleic acids in this conformation have important but so far uncharacterised biological functions. One such protein is the innate immune protein Z-DNA binding protein-1 (ZBP1/DAI/DLM1). We have evidence that ZBP1 mediates virus-induced necroptosis in a manner dependent on its ZBD. This function of ZBP1 is sensitive to RNase but not DNase treatment, suggesting that the trigger is Z-RNA. We therefore hypothesise that Z-RNA may represent a novel pathogen-associated molecular pattern sensed by ZBP1. The aim of my PhD will be to further characterise this role of ZBP1 and to investigate the source and nature of the Z-RNA being sensed. In particular, we will ask if this Z-RNA is of viral and/or cellular origin, and whether specific sequence motifs are recognised by ZBP1. Another question pertains to the relevance of ZBP1 in diverse human virus infections. In parallel to these <em>in vitro</em> studies, we are developing a knock-in mouse in which the ZBD of ZBP1 is mutated. I predict that these animals will be less able to control viral infection due to a failure of ZBP1-mediated virus-induced necroptosis.</p>

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

Not just a virulence factor: capsule biology across the Neisseria genus 31 Jan 2017

<p>This project seeks to address the relatively unexplored topic of the genetics, function and evolutionary history of the&nbsp;<em>Neisseria</em> polysaccharide capsule, beyond its established role as a virulence factor in<em> Neisseria meningitidis </em>(Nme). This will be achieved by examining capsular types not associated with disease, both from Nme, and capsules recently discovered in the commensal <em>Neisseria </em>species. The first goal is to complete genetic and phenotypic characterisation of the novel commensal capsular types. Once this is established, a key goal is to seek comparisons between these novel capsules and those of Nme within the coding sequences and regulatory regions, and at the structural level. I also plan to address the question of what the role of capsule is in colonisation and transmission, given that it most likely was not selected for its virulence properties. Finally, I seek to build a clearer history of the acquisition and evolution of capsule in <em>Neisseria.</em> This will bring forward new insights into the roles of capsule in normal, healthy colonisation of the nasopharynx, both by Nme and the strictly commensal <em>Neisseria </em>species. This work may also have implications for our interpretation of Nme dynamics and the rare transition to a state of disease.</p>

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

The role of regulatory T cells in immunity to malaria 31 Jan 2017

<p>In malaria vaccine trials conducted in the target population of semi-immune people from endemic African countries, vaccine immunogenicity is sometimes substantially reduced compared to European malaria-na&iuml;ve participants. This could result from the suppression of vaccine-induced immune responses by regulatory T cells (Tregs) acquired through prior malaria infections, however there are few studies in man which have previously explored this. Using samples from controlled human malaria infection studies in semi-immune Kenyan individuals, we will investigate how Tregs affect natural immunity to infection and see if increased Treg responses correlate with vaccine efficacy following malaria challenge in participants with varying prior exposures to malaria. We will also directly compare the effect and induction of Tregs in different pre-erythrocytic candidate vaccines and adjuvants to understand how vaccine-specific effects might affect Treg responses. Additionally, we will investigate if malaria-induced Tregs affect responses to other childhood vaccines. Single cell transcriptomic analysis using the Fluidigm platform will be employed to explore the phenotype and functional heterogeneity of Tregs. This will provide insight into the mechanisms by which Tregs are involved in immunity to malaria. This work will have important implications for the design and evaluation of malaria vaccines for use in endemic populations.</p>

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

How the protein antibiotic pyocin S5 kills Pseudomonas aeruginosa 31 Jan 2017

<p>With the rise in multidrug resistance as a result of broad spectrum antibiotic use, bacteriocins have received attention as potential new antibiotics. Bacteriocins are bacterial toxins that kill closely related strains and species. Pyocin S5, a bacteriocin targeting <em>Pseudomonas aeruginosa</em>, a leading cause of multidrug resistant nosocomial infections, was shown to be effective against pneumonia in mice.</p> <p>Pyocin S5 depends on the iron receptor FptA and kills cells by depolarizing the inner membrane. Little else is known about its mode of action. Pyocin S5-producing cells harbour a gene encoding a small immunity protein, predicted to localize to the inner membrane, which protects from the action of this pyocin.</p> <p>In this PhD project, I aim to investigate the molecular mechanism of pyocin S5 binding to <em>P. aeruginosa</em> cells, its mechanism of translocation to the periplasm and the immunity protein&rsquo;s mode of action. These aims will be approached using a combination of structural and biophysical methods as well as functional assays and a variety of fluorescence microscopy techniques.</p>

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

Functional diversity and plasticity of mucosal-associated invariant T cells 31 Jan 2017

<p>Mucosal-associated invariant T (MAIT) cells are innate-like T cells that express a semi-invariant, MR1-restricted, T cell receptor (TCR).&nbsp; In humans, they comprise 1-10% of peripheral blood T cells and are enriched at mucosal sites.&nbsp; MAIT cells display characteristic expression of several surface molecules and transcription factors, and a typical cytokine response to stimulation.&nbsp; Therefore, they have been regarded as relatively homogeneous.&nbsp; However recent evidence indicates diversity in TCR expression and function that varies between tissues and individuals.&nbsp; Further investigation is required to understand the extent of MAIT cell heterogeneity and tissue-specific functionality.&nbsp; In several human autoimmune and inflammatory diseases, MAIT cells are activated or show phenotypic changes.&nbsp; How the altered cytokine environment in such diseases can modulate MAIT cell function remains to be determined.&nbsp; The key goals of my research are to provide a comprehensive assessment of diversity and plasticity in MAIT cell function, and to understand the factors that regulate this.&nbsp; To achieve this, I will use a combination of approaches including single-cell mRNA sequencing and epigenetic analysis, and will explore MAIT cells from varied settings encompassing resting and activated, tissue-localised, and disease-associated MAIT cells.&nbsp; This will provide important insights into their physiological role both in health and disease.</p> <p>&nbsp;</p>

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

The role of motor learning and sleep in the modulation of structural and functional long-range connectivity in the rodent brain 31 Jan 2017

<p>Learning new motor skills can trigger new myelin synthesis and induce changes in long-range structural and functional connections in the adult brain. Understanding the biological basis of neuroplasticity is critical for developing interventions for brain injury. It is still not clear, however, whether these structural and functional changes are related. It is also critical to find strategies to boost myelination and to identify whether it can support other types of learning. We aim to address these caveats by running three experiments. Firstly, we will investigate whether motor skill training increases electrophysiological coupling in somatosensory and motor task-relevant areas and whether this relates to changes in white-matter (WM) structure. We will also assess whether the deletion of the myelin regulatory factor (MyRF) can impair these processes. Secondly, sleep has been found to promote motor learning consolidation. We will study the role of sleep in these possible behavioural, WM and functional coupling changes by contrasting the effects of sleep and sleep deprivation in wild-type mice trained in a motor skill paradigm. Thirdly, we will investigate whether myelination is required for hippocampal-dependent learning by assessing the effects that training induces in WM structure and testing whether deleting MyRF or neurogenesis affects this process.</p>

Amount: £65,753
Funder: The Wellcome Trust
Recipient: University of Oxford

Defining how different types of midbrain dopamine neuron mediate behaviour in the contexts of reward and aversion 31 Jan 2017

<p>Learning the value of actions based on prior experience is critical for adaptive behaviour. Rewarding and aversive stimuli have opposite motivational valence, with evidence suggesting that the phasic firing of distinct groups of midbrain dopamine neurons differentially encodes reward and aversion as a function of their projection target. My first research aim is to elucidate the molecular signatures of subpopulations of dopamine neurons innervating the nucleus accumbens or prefrontal cortex. To achieve this, I will combine injections of retrograde tracers with immunofluorescence revelation of molecular markers in mice. My second aim is to determine how distinct types of dopamine neuron, as defined by their specialised molecular profiles and projection targets, encode behaviour. To achieve this, I will carry out recordings of individual molecularly-identified neurons in head-fixed mice as they perform a classical conditioning task incorporating rewarding and aversive events. My third aim it to elucidate a causative role for a specific subpopulation of dopamine neurons in behaviour. To achieve this, I will use an optogenetics-based approach to inhibit these neurons in behaving mice. Overall, this research project is predicted to advance understanding of how different subpopulations of midbrain dopamine neuron subserve behaviour in the context of reward and aversion.&nbsp;</p>

Amount: £31,243
Funder: The Wellcome Trust
Recipient: University of Oxford

Inducing and disrupting white matter plasticity 31 Jan 2017

<p>Recent evidence has shown that dynamical changes in white matter underlie the learning of motor skills. This has been observed both in humans with Diffusion Tensor Imaging (DTI, Schulz et al., 2009) and in rodents with histology (Sampaio-Baptista et al., 2013). These findings raise questions on which conditions are necessary for WM plasticity induction and how the plasticity they induce is modulated by genetic factors.</p> <p>&nbsp;</p> <p>Can an artificial induction of white matter plasticity in humans lead to behavioural changes, even without actual motor experience? To answer this question, the first aim of my DPhil will be to induce white matter plasticity at rest; more specifically, I will attempt to do so through fMRI neurofeedback, and will monitor the outcome with DTI and other myelin-specific MRI modalities.</p> <p>&nbsp;</p> <p>Given that white matter is often implicated in psychiatric disorders, a second question regards whether genes related to mental health conditions (in this case, NR1), can influence how white matter responds to learning, and possibly underlie a deficient or maladaptive response. Therefore, the second aim of my DPhil will be to investigate whether WM plasticity is affected in a mouse model of white matter-specific knockout of NMDA receptors.</p>

Amount: £83,102
Funder: The Wellcome Trust
Recipient: University of Oxford

Formation and representation of motor-auditory associations in mouse auditory cortex 31 Jan 2017

<p>Studies of sensorimotor integration have long focused on &ldquo;hard-wired&rdquo; actions such as eye movements and vocalizations, but have only recently been extended to more complex learned behaviours such as locomotion and navigation - and so far only in the visual domain. Nevertheless, in order for an animal to successfully navigate through an acoustic environment containing dynamic sound sources at different locations, it is critical that sensory predictions coming from its own locomotion are compared with actual sensory feedback. To investigate this type of sensorimotor learning, I plan to build a close-loop spatial hearing set-up for head-fixed behaving mice, and to train mice to navigate in a virtual &lsquo;sound maze&rsquo; using spatially localized sound sources. I then propose to track the population dynamics of neurons in auditory cortex, as the animal learns to create motor-auditory associations, using two-photon laser scanning microscopy in transgenic mouse-lines. In doing so, I will search for neurons encoding mismatch between expected and actual auditory feedback, characterizing their spatial distribution and response properties. Finally, I aim to investigate the neural circuitry underlying motor-auditory integration by imaging axonal projections from motor cortex and thalamus towards excitatory and inhibitory neuronal subpopulations in auditory cortex.</p>

Amount: £46,094
Funder: The Wellcome Trust
Recipient: University of Oxford

The role of intra-area and inter-area neuronal interactions in the formation of perceptual decisions 31 Jan 2017

Humans and animals have to make decisions based on the integration of sensory information in order to thrive. In primates, neuronal activity in sensori-motor parietal area LIP has been proposed to reflect the accumulation of sensory information from a range of areas to make a perceptual decision. The change in firing rates has been described as an integration process with a diffusion-to-bound model or alternatively as step-like changes. This project aims to gain a better understanding of the neuronal processes underpinning perceptual decision-making and to test the universality of the proposed models. Simultaneous recordings with multiple probes from cortical areas LIP and V5/MT while animals solve a stereo-motion task will measure neuronal interactions (i) within LIP and (ii) with V5/MT. Extrastriate visual area V5/MT is important for the perception of motion as well as stereovision and has anatomical connections with LIP. Combined electrical stimulation and recording will establish the interaction of signals between these areas. I will also incorporate contextual effects into task and model to develop a realistic network model of how decision signals arise and shape cognitive function. This model can be applied to and tested with other brain areas and cognitive tasks.&nbsp;

Amount: £118,930
Funder: The Wellcome Trust
Recipient: University of Oxford

Dissecting Polo kinase recruitment to the centrosome 31 Jan 2017

<p>Polo kinase is an important cell cycle regulator and it is essential for the correct assembly of centrosomes, major cell organisers. Centrosomes are formed by a pair of cylindrical centrioles surrounded by pericentriolar material (PCM). Polo controls PCM assembly (at least in part through Cnn phosphorylation) and also centriole disengagement and assembly. How Polo is recruited to centrioles and centrosomes is mysterious. During my rotation I have obtained evidence that the PCM protein Spd-2 is necessary for Polo recruitment to centrosomes. During my project I aim to characterise if Polo binding to Spd-2 is necessary for Cnn phosphorylation and correct PCM organisation, what happens when Spd-2 cannot bind Polo and what upstream regulators facilitate this interaction. Furthermore, I aim to identify the other centriole/centrosome proteins involved in Polo recruitment. To do this, I will make use of biochemical assays and advanced microscopy techniques, coupled with fly genetics and a powerful mRNA injection assay to rapidly test the effects of different mutants in fly embryos. Ultimately, I hope to be able to describe in molecular detail which proteins are phosphorylated by which kinases to allow Polo to be recruited to fulfil its many functions at the centrioles and centrosomes.</p>

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