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Recipients:
University of Oxford

Results

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

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.

Amount: £1,048,938
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 and functional dissection of the RH5:CyRPA:RIPR complex required for erythrocyte invasion by Plasmodium falciparum 05 Dec 2016

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

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

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

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

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

Structural studies of bacterial nucleic acid transport proteins 31 Jan 2017

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

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

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

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

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

Chemogenetic silencing of nociceptor populations 31 Jan 2017

Nociceptors are heterogeneous sensory neurons and due to single cell sequencing, our understanding of their diversity is expanding. To understand which nociceptor populations are responsible for different pain-related behavioural phenotypes, we aim to employ a chemogenetic silencing tool to allow reversible inhibition of selected cells in vivo. Our chemogenetic tool of choice is the mutated glutamate-gated chloride channel (GluCl). Initially, we expressed the channel in cultured DRG neurons and using patch-clamp recordings observed dose dependent silencing upon application of the agonist ivermectin (IVM). We have optimised the channel and assessed channel functionality in vitro and in vivo following AAV-mediated delivery. Behavioural assays suggest IVM treated animals had significantly elevated pain thresholds compared to vehicle treated mice. Using rodent pain models (SNI, CCI) in conjunction with conditioned place preference tasks, we aim to further establish this method of nociceptor silencing as a potential therapeutic. Furthermore, to understand nociceptor heterogeneity our first target population will be the A-delta nociceptors. Using transgenic strategies we hope to selectively express GluCl in A-delta nociceptors and perform electrophysiological and sensitive behavioural assays pre and post IVM treatment. Ultimately this project aims to facilitate the discovery of novel nociceptor populations, their roles and their therapeutic potential.

Amount: £31,040
Funder: The Wellcome Trust
Recipient: University of Oxford

Early lineage decisions during mouse gastrulation 31 Jan 2017

Diversification of mesoderm and endoderm subtypes occurs at the outset of mouse gastrulation as epiblast cells migrate through the primitive streak (PS). The underlying inductive signals, gene-regulatory networks, and epigenetic modifications that direct lineage diversification at this early stage remains ill-defined. The aim of this project is to dissect the molecular mechanisms that underpin cell fate diversification, as cells egress the PS, by investigating the function of T-box transcription factors (TF), Eomesodermin (Eomes) and Brachyury (T). Eomes and T are expressed in the PS and Eomes is required for specification of cardiac mesoderm (CM) and definitive endoderm (DE). Single cell lineage tracing and RNA-seq experiments will be completed to define the potency and heterogeneity of Eomes and T expressing progenitors. The functional role Eomes plays in haematopoiesis will also be investigated using multiple gain and loss of function experiments. Finally, we will investigate context dependent Eomes binding sites and interacting partners. Eomes tagged mouse embryonic stem cells (mESC) will be differentiated into CM or DE progenitors and with them we will perform ChIP-Seq, RNA-Seq and immunoprecipitation-mass spectrometry(IP-MS). The experiments proposed will help resolve the functional and molecular roles T and Eomes play during early stages of lineage diversification.

Amount: £45,812
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 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.

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

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

This project seeks to address the relatively unexplored topic of the genetics, function and evolutionary history of the Neisseria polysaccharide capsule, beyond its established role as a virulence factor in Neisseria meningitidis (Nme). This will be achieved by examining capsular types not associated with disease, both from Nme, and capsules recently discovered in the commensal Neisseria 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 Neisseria. 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 Neisseria species. This work may also have implications for our interpretation of Nme dynamics and the rare transition to a state of disease.

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

The evaluation of effective healthcare delivery in China using electronic medical records for 10 years in 0.5M participants in the China Kadoorie Biobank 02 May 2017

This DPhil project will assess the social determinants and equality in hospital care delivery and use, in 0.5 million participants who have been followed up for 10 years in the China Kadoorie Biobank. The first goal of this research is to evaluate differences in the annual rates of people hospitalised, the annual rates of hospital admissions per person, and the average length of stay (ALOS) overall and for 10 of the most frequent causes of hospitalisation (5 mostly unavoidable and 5 mostly avoidable causes) over the last 10 years and by region, hospital-tier, type of health insurance (HI) package and socioeconomic characteristics. Another goal is to study the variation in hospital care costs in China, considering LOS, and use of specialised procedures and major treatments, overall and for the 10 most frequent causes of hospitalisation over the last 10 years, by region, hospital-tier, HI package, and socioeconomic characteristics. Finally, the inequalities behind the variation in use and costs of hospital care will be investigated across regions, HI package and socioeconomic characteristics. This will provide the reliable quantitative evidence to evaluate operational defects and plan initiatives to improve healthcare delivery by individual hospitals, HI organisations and the wider community in China.

Amount: £95,184
Funder: The Wellcome Trust
Recipient: University of Oxford

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

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 – through small grants and offering training and mentoring. We have had a good uptake of these ‘seed awards’ from MOP researchers and increasing interest in engagement from researchers at local institutes in Vietnam. 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’s magazine; science theatre; and lab visits enabling young people to interact with scientists. The SEP has also included ‘I’m a scientist, Get me out of here’ - 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 ‘front-line’ 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.

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

Healing Heathen Lands: Protestant Missions and Public Health in British India, 1855-1956 17 Jul 2017

This project will explore the role of Protestant missions in the making of British Indian public health by tracing the interactions between evangelical, colonial and vernacular sources. It will argue that Protestant missionaries in South Asia did not merely play a complementary role to imperial biomedicine. It will examine the ways in which missions contributed towards shaping colonial health policies as well as knowledge of colonial disease and treatment. The project would also explore the extent to which Indians and their knowledge was involved in medical missions. This work will add on to histories of imperial medicine, international health, global history, colonial Christianity and postcolonial studies. The key goal of the project is to produce a monograph explaining the distinctiveness and significance of Protestant missionary medicine in South Asia. The project will be contributing to the emerging literature on British voluntary religious organisations in the making of imperial public health. It will also contribute to the broader literature on the relationship of modern science and medicine with Christianity.

Amount: £174,774
Funder: The Wellcome Trust
Recipient: University of Oxford

The Opie archive: exploring play in Britain from the 1950s to the 1980s 25 Nov 2016

This project focuses on the archive of internationally renowned folklorists Iona (b. 1923) and Peter Opie (1918-1982). The Opies' landmark publications were based on information contributed by some 20,000 children from schools all over Britain, in response to three surveys (c.1950–80), supplemented by the Opies’ own in-depth observation and sound recording, of a wide variety of games and forms of play. The Opie archive at the Bodleian includes the survey responses, correspondence, and the Opies’ loose-leaf research files. At present, this collection can only be searched by physically looking through the papers. It is consequently little used, even by specialists. At the same time, even limited use results in wear and tear of a collection which is vulnerable to the possibility of damage through mishandling or misfiling. Our goal is threefold: One, to unlock this archive's full potential by creating a catalogue, and physically preparing the archive for a future digitisation project, which will permit creative uses of the content without endangering the original materials. Two, to publicise the archive in its usable form to a wide range of audiences and encourage increased and diverse use. Three, detailed scoping of digitisation possibilities in collaboration with intrerested academic partners.

Amount: £102,382
Funder: The Wellcome Trust
Recipient: University of Oxford

Stochastic variation and regulation of bacterial DNA repair and mutagenesis 30 Sep 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: £25,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Utilising snake endogenous toxin inhibitors for the development of improved antivenom treatments 09 Nov 2016

Snake envenoming causes significant annual mortality, predominantly in the developing world. Currently the only effective treatment is antivenom, which is produced by hyperimmunising large animals with crude venom, and then extracting and purifying the antibodies raised against the snake proteins. This method requires keeping and maintaining large numbers of livestock, a key contributor to the high cost. Furthermore, the efficacy of antivenom is completely dependent on the venom sample(s) utilised for production, and the animal-derived antibodies can cause unwanted immunogenic effects in the patient, such as anaphylaxis. This project aims to make steps towards developing new antivenom treatments by utilising the endogenous toxin inhibitors used by snakes to protect themselves from their own venom. First, both the toxin and toxin inhibitor repertoire of 5 species of venomous snake will be elucidated using multi-'omic' technologies. Candidate inhibitors will be expressed in human cell lines, and subsequently tested experimentally to determine their efficacy in neutralising venom effects which cause the most life-threatening pathology. This method will revolutionise the antivenom field, and pave the way to developing treatments which are more cost effective, have fewer side effects, require no live animals, and have a greater and wider efficacy in treating snakebite.

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

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