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Recipients:
University of Oxford
Award Year:
2017
Currency:
GBP

Results

Regulated mRNA stability and translation in neural stem cell development 28 Nov 2017

Understanding how the billions of varied cells in the human brain develop from a small number of neural stem cells (NSCs) is a central question in biology and medicine. This highly complex process has largely been explained by transcriptional regulation dictating the levels of protein expression in stem cells and their progeny. Using novel single molecule approaches to quantitate transcription and protein levels, we have discovered functionally important conserved examples where the levels of transcription and protein expression do not correlate. These include pros/prox1, the regulator of NSC proliferation and differentiation and myc, the proto-oncogene regulator of stem cell size. We will characterise the mechanism of post-transcriptional regulation of pros, myc and 21 additional functionally important examples we have discovered, all of which have extremely long 3’UTRs that are bound and regulated by the same conserved RNA binding proteins, Syp and Imp. We will also measure, genome-wide, mRNA stability and characterise the trans-acting factors and cis-acting signals regulating stability and translation. The proposed programme will characterise a hitherto under-studied layer of regulation acting in addition to transcription in complex tissues, providing major new mechanistic insights into how the brain develops in health and disease.

Amount: £1,972,007
Funder: The Wellcome Trust
Recipient: University of Oxford

Dengue Controlled Human Infection Model - Development Grant 17 Nov 2017

Following a positive response to the preliminary submission for grant funding to establish a Dengue Controlled Human Infection Model (Dengue-CHIM ) in Ho Chi Minh City, Vietnam, I am submitting this request for a small grant to assist in refining and developing the main proposal prior to final submission in March 2018. During this pre-submission phase I plan to employ an experienced post-doctoral immunologist to carry out a) a scoping review of the current landscape of dengue vaccines in development, and b) a review exploring the current understanding of the immune response to/protection from DENV infection and disease, particularly focusing on immune correlates of protection. This will be the first application of a Dengue-CHIM approach in any dengue endemic setting, and raises a number of important bioethical concerns. Therefore I also plan to employ a Vietnamese social science research assistant for a period of 4 months to engage with key Vietnamese stakeholders to discuss the important issues surrounding endemic setting CHIMs, conduct preliminary informal interviews with these individuals, and help to develop the agenda for a 2 day workshop focused on Bioethics and Stakeholder Engagement related to endemic setting CHIMs that will take place in early March.

Amount: £23,690
Funder: The Wellcome Trust
Recipient: University of Oxford

Molecular control of pathogenic neutrophil responses in inflammation 28 Nov 2017

Neutrophils cause immunopathology by overproducing anti-microbial activities that may lead to tissue damage in inflammatory and autoimmune diseases, including rheumatoid arthritis, vasculitis, and lupus. Recent data highlight the existence of neutrophil subsets with different pathogenic properties. However the molecular control of pathogenic neutrophil responses is largely unknown. We will identify the intrinsic transcriptional circuitry that controls neutrophil functional reprogramming and provide insights into neutrophil heterogeneity and pathogenic phenotypes at sites of inflammation. Our recent studies highlighted a number of candidate transcription factors that will be functionally validated during the course of this project. Our work and the results of others have shown that neutrophil accumulation in tissues during sterile inflammation is controlled by macrophages. We will characterise how protein and lipid signals produced by monocytes and macrophages in the tissue at the different stages of inflammation affect neutrophil accumulation and activation and whether these are under a unified transcriptional control. Understanding the control of pathogenic neutrophil responses and identification of key regulators of immunopathogenic phenotypes will help to redefine these understudied cells in chronic inflammatory disorders and may lead to new treatments reducing the burden of human chronic inflammatory disease.

Amount: £1,541,677
Funder: The Wellcome Trust
Recipient: University of Oxford

Decoding the molecular identity of neurons 28 Nov 2017

Regulated gene expression underlies the specification of cell fate and the maintenance of cell-specific function. Cellular diversity is of particular importance in the brain where neural circuits are assembled from cells with unique properties. Many neurological and psychiatric conditions arise from dysfunction in the brain, and although molecules are the targets of therapeutic drugs, we know relatively little about those that are critical for specific neural functions. Here we propose to generate a single-cell resolution transcriptome of the entire fly brain using Drop-seq. In a unique collaborative effort we will mine this data set to uncover molecules that contribute to an array of important neural processes, including: 1. How does Kenyon cell diversity support memory-guided decisions? 2. What is the extent of input specificity to functionally discrete dopaminergic neurons? 3. How do particular peptidergic neurons respond to internal states? 4. How does sex-specific neuronal identity emerge? 5. Is there a rational transcription factor logic for cell-specific gene expression? Our endeavour also possesses significant technological value. Transcriptomic information, and the design of synthetic regulatory sequences that decode cell-specific patterns of gene expression, will improve the precision and resolution with which experimental effector genes can be targeted to pre-determined groups of neurons.

Amount: £3,500,000
Funder: The Wellcome Trust
Recipient: University of Oxford

The Animal Research Nexus: Changing Constitutions of Science, Health and Welfare 01 Feb 2017

This five-year collaborative programme will develop approaches for understanding laboratory animal research as a nexus, asking how reconceptualising connections and generating communication across different perspectives can contribute to improving the future of animal research. New research will draw attention to historical independencies between science, health and welfare; identify challenges emerging at the interfaces of animal research and create opportunities for informing policy and public engagement. We suggest collaborative approaches are essential for understanding how rapid transformations across science and society are changing the patterns of responsibility, trust and care which hold together, or constitute, this nexus. We will deliver new: integrated research across the social sciences and humanities, using historical research to inform understanding of present challenges and create new engagement opportunities for the future; interactive research projects, co-produced with researchers, animal suppliers, veterinarians, publics and patients, to investigate the contemporary dynamics of animal research; interfaces for generating cultures of communication with publics, policy-makers and practitioners across the animal research nexus. This programme brings together five leading researchers on the social and historical dimensions of animal research, uniting the strengths of five institutions, engaging creative practitioners, and advancing the work of five early career researchers and three PhD students.

Amount: £336,137
Funder: The Wellcome Trust
Recipient: University of Oxford

Discretionary Award 30 Sep 2017

'Sacred Water' – an engagement project run by artist Lena Bui, was a creative space for researchers at OUCRU-Nepal and people living in the Kathmandu Valley to discuss health with a focus on water. However, the earthquake of 2015 caused many participants to reflect on a wider view of health. Lena became interested in what people turn to for a sense of wellbeing - cultural rituals, western medicine, traditional healers, astrologers, or god. She developed a script based on personal accounts and will now continue the collaboration with OUCRU-NP and the local community to develop the project into an exhibition with a feature-length film as an exploration of health beyond the functioning of a physical body. The film, A Vertical Walk, is a mixture of documentary, travelogue, essay video and experimental images, taking the viewers through landscapes shaped by accounts and fragments of dreams and memories. A public exhibition, held in Kathmandu, will consist of the film, animations, larger paintings and open discussions with the artist and researchers. We will collaborate with a local venue to create a space promoting reflection on the essence of resilience and the role of culture and faith in our existence and sense of wellbeing.

Amount: £40,000
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

Investigating the mechanisms and elements responsible for nuclear compartmentalisation during gene regulation. 31 Jan 2017

The genome is organised into a highly ordered and complex structure. It is separated into distinct regulatory compartments which have a functional impact on transcriptional regulation. CTCF has been found to act as a boundary, with the ability to block enhancer-promoter interactions and insulate regulatory territories. The process that creates and regulates this genome organisation is not well understood, therefore, the main aim of the proposed research is to investigate the role of CTCF, enhancer and promoter elements in generating and defining regulatory domains. To achieve this, we will initially expand a series of models mutating the CTCF sites within the well characterised mouse alpha-globin locus, and explore genome-wide, polymorphic CTCF binding sites between inbred mice strains. The effects on local chromatin and transcription will be assessed using a combination of standard genomic assays used within the Hughes group, and the chromosome conformation capture technique NG Capture-C developed by them. To complement this, we will use genetic engineering to find the minimal requirements for compartment formation using the well-characterised functional elements from the mouse alpha-globin locus out of their native chromosomal context, to define the basic rules underlying their formation.

Amount: £35,176
Funder: The Wellcome Trust
Recipient: University of Oxford

Dissecting Polo kinase recruitment to the centrosome 31 Jan 2017

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.

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

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.

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

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

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 Pseudomonas aeruginosa, a leading cause of multidrug resistant nosocomial infections, was shown to be effective against pneumonia in mice. 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. In this PhD project, I aim to investigate the molecular mechanism of pyocin S5 binding to P. aeruginosa cells, its mechanism of translocation to the periplasm and the immunity protein’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.

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

Epidemiology and health burdens of antimicrobial resistant bacterial infection in Southeast Asia and impact of antibiotic use on patient survival 19 Jun 2017

Epidemiology of drug-resistant infection (DRI) and impact of antibiotic use on patient mortality remain largely unknown in Southeast Asia. Correction factors are crucial to estimate the total deaths attributable to DRI when only mortality of patients with bacteraemia is known. The correction factors are available for developed country and not for developing country. I aim to establish correction factors for developing country. I also aim to study the epidemiology of drug-resistance and estimate the number of excess deaths attributable to DRI in Southeast Asia. Most studies on the impact of inappropriate antibiotic use on mortality were conducted in high-income countries, and methods used were vulnerable to biases. Neglecting both the time-varying nature of contributing factors; including risk of DRI over time, and the effect of antibiotic overuse on risk of DRI in other patients could misestimate the impact of antibiotic use on patient mortality. I aim to use advanced statistical models to overcome the potential biases, and to estimate and compare the impact of appropriate and inappropriate antibiotic use in Thailand and Vietnam against that in the United Kingdom where antibiotic stewardship is well established. These are important to assist designing and assessing of antibiotic stewardship programme in developing countries.

Amount: £18,800
Funder: The Wellcome Trust
Recipient: University of Oxford

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

The MYRIAD Project: Exploring Mindfulness and Resilience in Adolescence

Amount: £250,800
Funder: The Wellcome Trust
Recipient: University of Oxford

Stochastic variation and regulation of bacterial DNA repair and mutagenesis 22 Feb 2017

Studying the molecular mechanisms of mutagenesis is crucial to understanding genome evolution and the emergence of drug resistance in pathogens. It is known that cellular stress responses increase mutation rates after DNA damage and antimicrobial treatment. Recent evidence suggests that stochastic effects play key roles in these responses, causing cell-to-cell variation in mutation rates and diversifying cell phenotypes to evade drug treatment. However, existing cell biology, biochemistry, and genetics assays fail to resolve mutation rate dynamics and cellular heterogeneity. By combining live-cell single-molecule microscopy, single-cell manipulation, and DNA sequencing techniques, I will bridge the divide between molecular-level and genome-level approaches. I will visualise mutagenic molecular processes in real-time and link them to genome sequence changes in individual bacterial cells. Ultimately, I will discover how individual mutation events are related to single-cell phenotypes such as DNA repair activities, stress responses, and growth characteristics. My focus will be on the conserved SOS response that globally regulates genome maintenance and has been implicated in the bacterial response to antibiotics. Using a novel method to quantify post-translational modifications of the master SOS regulator, I will uncover the molecular choreography of the SOS response and establish how it contributes to the evolution of antibiotic resistance.

Amount: £1,120,177
Funder: The Wellcome Trust
Recipient: University of Oxford

The role of diurnal intracellular chloride changes in cortical network activity and plasticity. 19 Apr 2017

Cyclical changes between sleeping and waking states are a fundamental feature of mammalian physiology. During these different states, our brains exhibit distinct patterns of network activity and different capacities to learn. An understanding of the cellular mechanisms that underlie these processes is important to fully appreciate how daily changes in brain function contribute in health and disease. Here I propose to explore how dynamic changes in synaptic inhibition influence the mammalian cortex across the sleep-wake cycle. This will entail experiments that span cellular and systems levels of neuroscience, and that capitalise on my experience in developing novel applications of optogenetic tools. Using the mouse as a model system, I will examine the hypothesis that diurnal changes in intracellular chloride contribute to sleep-wake associated changes in cortical brain states and synaptic plasticity. To achieve this, my key goals are as follows. (i) I will establish the cellular and systems mechanisms that regulate the diurnal variation of intracellular chloride in mouse cortex. (ii) I will examine how diurnal chloride variation affects cortical network oscillations across the sleep-wake cycle. (iii) I will investigate the physiological impact of diurnal chloride variation upon cortical synaptic plasticity, by examining learning mechanisms during the day and night.

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

Epidemiology and health burdens of antimicrobial resistant bacterial infection in Southeast Asia and impact of antibiotic use on patient survival 19 Jun 2017

Epidemiology of drug-resistant infection (DRI) and impact of antibiotic use on patient mortality remain largely unknown in Southeast Asia. Correction factors are crucial to estimate the total deaths attributable to DRI when only mortality of patients with bacteraemia is known. The correction factors are available for developed country and not for developing country. I aim to establish correction factors for developing country. I also aim to study the epidemiology of drug-resistance and estimate the number of excess deaths attributable to DRI in Southeast Asia. Most studies on the impact of inappropriate antibiotic use on mortality were conducted in high-income countries, and methods used were vulnerable to biases. Neglecting both the time-varying nature of contributing factors; including risk of DRI over time, and the effect of antibiotic overuse on risk of DRI in other patients could misestimate the impact of antibiotic use on patient mortality. I aim to use advanced statistical models to overcome the potential biases, and to estimate and compare the impact of appropriate and inappropriate antibiotic use in Thailand and Vietnam against that in the United Kingdom where antibiotic stewardship is well established. These are important to assist designing and assessing of antibiotic stewardship programme in developing countries.

Amount: £184,563
Funder: The Wellcome Trust
Recipient: University of Oxford

Evidence for a pathogenic link between lung inflammation and autoimmune arthritis 27 Apr 2017

Our overall objective is to experimentally identify the early immunological events which trigger a spontaneous breach of tolerance in genetically susceptible mice, and, which can be linked to the development of arthritis. We will analyse the immunological reactivity of the lungs of susceptible mice to environmental stresses such as microbes. Our purpose is to identify early biomarkers of autoimmune initiation, which will be assessed for suitability as treatment targets with translational relevance. We will seek to determine the benefits of administration of anti-microbial agents for amelioration of lung inflammation with a view to prevention of autoimmune disease progression.

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

Myeloid effector cells in inflammation 27 Apr 2017

Dysregulation of inflammation underlies a range of chronic inflammatory disease. By increasing our understanding of inflammatory mechanisms we may be able to identify specific therapeutic targets to treat disease. Using a murine model of acute, resolving inflammation, with zymosan as stimulus, we create a physiological inflammatory system where we can observe the spatiotemporal relationship of monocytes, macrophage and neutrophils which predominate this response. These observations in a controlled setting will give us insights into how these cells interact to orchestrate an inflammatory response. Gain of function IRF5 is associated with a range of autoimmune and inflammatory disease and promotes an pro-inflammatory phenotype in monocytes and macrophages. We will manipulate the system using mice deficient of IRF5 to modulate the monocytes phenotype and will be able to study the impact on neutrophil function and activation. These findings have the potential to be translated into more complex physiological systems and present new pathways for the study of disease.

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

Design and development of a breathing powered prosthetic prototype 27 Apr 2017

The input required to control a prosthetic device greatly defines the subsequent precision that can be achieved. Robust mechanisms that are low-cost often use musculoskeletal motion for control. However, this often limits the level of control and applicability issues can arise when the system that is augmented also generates the power and drives the control. A device that is powered and controlled by breathing could expand the product options for patients and address certain requirements that are difficult to meet with the currently available prosthetic solutions. Computational modelling has been applied to asses if a Tesla turbine can be used for power and control. Positive results from the model and subsequent conceptual testing has indicated this innovative concept could indeed provide precision control for prosthetic users. The aim of the project is to design and produce a working prototype and test out the functional capabilities of the system using several predetermined tasks.

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

Combining genetics and high-resolution cell phenotyping to map pathways underlying inflammatory bowel disease 18 Oct 2017

Inflammatory bowel disease is a chronic, difficult to treat condition with unknown underlying causes. Given its high heritability, understanding IBD biology requires understanding how genetic risk variants impact the immune system. This project aims to identify measurable immune phenotypes through which IBD risk variants act, and investigate the impact of these phenotypes on disease prognosis. My first objective is to prioritize immune pathways where IBD genes are active, and develop methods of quantifying these pathways by phenotyping specific immune cells. I will use new statistical techniques to infer these pathways, single-cell analysis to discover impacted cell types, and collaborations with immunologists to establish phenotyping techniques. My second objective is to demonstrate associations between risk variants and candidate immune pathways. We will measure gene expression and readouts of immune function on IBD-associated cell types in 200 genotyped patients and 200 controls, and carry out eQTL, association and risk score analyses. My final objective is to build the groundwork for translating these discoveries into new treatments. We will test whether immune phenotypes predicted disease flares in our patients, and if so work with clinicians to design stratified medicine trials. We will work with partners to investigate future therapeutic interventions for these pathways.

Amount: £1,161,290
Funder: The Wellcome Trust
Recipient: University of Oxford