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

Results

Understanding the link between CpG islands and gene transcription 28 Nov 2017

CpG islands(CGIs) are epigenetically specified elements that are intimately associated with over two-thirds of human gene promotors, yet whether CGIs regulate gene expression has remained enigmatic. This gap in our understanding of gene promoter function has serious implications for human health given that CGIs are perturbed in cancer and other debilitating human diseases. We have recently discovered that CGIs are recognized by reader proteins which can regulate gene expression. Capitalising on these advances, I will now discover how CGIs and the proteins that read them control the transcriptional machinery at gene promoters. I will achieve this transformative new mechanistic understanding through a multidisciplinary and hypothesis-driven programme of research that builds on a series of exciting new and unpublished observations to discover how CGIs function to activate(Aim1) and maintain(Aim2) transcription, and test whether CGIs create gene expression switches(Aim3). These new discoveries will help to redefine our understanding of how gene promoters function to control gene expression and will provide the basis on which new therapeutic interventions can be developed for diseases where normal CGI biology is perturbed.

Amount: £2,072,282
Funder: The Wellcome Trust
Recipient: University of Oxford

How does the Pericentriolar Matrix function in Centrosome Biology? 28 Nov 2017

Centrosomes are the major microtubule organising centres in many animal cells. They form when centrioles assemble an electron dense matrix of pericentriolar material (PCM) around themselves. Several hundred proteins are concentrated in the PCM, including many cell-cycle regulators and cell signalling molecules, and centrosomes function as important coordination centres within the cell. The underlying principles that allow centrioles to recruit and organise the many proteins required to form a functional centrosome are largely mysterious. Recent studies from our laboratories have identified a surprisingly simple pathway of mitotic centrosome assembly that is conserved in flies and worms. The centriole and PCM protein Spd-2/SPD-2 recruits the mitotic kinase Polo/PLK1 and the large coiled-coil protein Cnn/SPD-5 around the mother centriole. Polo/Plk1 then phosphorylates Cnn/SPD-5, allowing it to assemble into a micron-scale structure that recruits other PCM proteins. Our studies suggest that Cnn/SPD-5 molecules phase-separate into a biomolecular condensate that functions as a "scaffold" that then recruits the many "clients" necessary for centrosome function. Our goal is to understand at the atomic level the nature of the interactions that drive the assembly of the mitotic centrosomal-scaffold, and, by comparting the two different model systems, to describe a conserved pathway for centrosome assembly.

Amount: £1,639,125
Funder: The Wellcome Trust
Recipient: University of Oxford

Timestamping Integrative Approach to Understand Secondary Envelopment of Human Cytomegalovirus 28 Nov 2017

The mechanisms facilitating the assembly of Human cytomegalovirus (HCMV) in the cytoplasm of infected cells, a complex process termed ‘secondary envelopment’, are poorly understood. Our goal is to identify in-situ the identity, position, and interactions of all the essential proteins involved in this critical stage of the viral ‘lifecycle’. Despite decades of research, it has been difficult to dissect the complexity of secondary envelopment, as bulk assays only show ensemble averages of populations of viral particles. To study these intermediates that are formed when cytoplasmic capsids acquire tegument proteins and their envelope membrane, we will develop a novel approach that separates these intermediates in time and space. We will provide their spatio-temporal models by integrating complementary cutting-edge techniques and expertise within this collaboration, including flow-virometry, correlative (fluorescence and electron cryo) microscopy, crosslinking and ion-mobility mass spectrometry-based proteomics, and computational modelling. Specifically, we aim to: -Identify key players in tegument assembly on capsids/membranes. -Elucidate the order and spatial organisation of tegument assembly. -Validate the interactions in vivo and analyse capsid tegumentation in vitro. -Integrate the information into a spatiotemporal model. This will significantly improve our understanding of herpesvirus assembly in general, a crucial step towards identifying new therapeutic targets.

Amount: £742,082
Funder: The Wellcome Trust
Recipient: University of Oxford

Molecular mechanisms of HIV-1 restriction by capsid-sensing host cell proteins 05 Apr 2017

Infections by retroviruses, such as HIV-1, critically depend on the viral capsid. Many host cell defence proteins, including restriction factors Trim5alpha, TrimCyp and MxB, target the viral capsid at the early stages of infection and potently inhibit virus replication. These restriction factors appear to function through a remarkable capsid pattern sensing ability that specifically recognizes the assembled capsid, but not the individual capsid protein. Using an integrative and multidisciplinary approach, I aim to determine the molecular interactions between the viral capsid and host restriction factors, TrimCyp and MxB, that underpin their capsid pattern-sensing capability and ability to inhibit HIV-1 replication. Specifically, I will combine cryoEM and cryoET with all-atom molecular-dynamics simulations to obtain high-resolution structures and atomic models of the capsid and host protein complexes (in vitro), together with mutational and functional analysis as well as correlative light and cryoET imaging of viral infection process (in vivo and in situ), to reveal the essential interfaces in their 3D organization for HIV-1 capsid recognition and inhibition of HIV-1 infection. Information derived from our studies will allow to design more robust therapeutic agents to block HIV-1 replication by strengthening the pattern recognition feature.

Amount: £1,476,229
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

Dynamics of canonical and variant PRC1 interaction with chromatin at single-molecule resolution 31 Jan 2017

Polycomb Repressive Complexes (PRC) 1 and 2 are protein complexes with histone modifying activity that are key to regulation of gene expression in eukaryotic development. PRC1 ubiquitylates H2A at lysine 119 (H2AK119Ub1), while PRC2 methylates H3 at lysine 27 (H3K27), that function together on chromatin, recognising the modification deposited by the other, suggesting a feedback loop. PRC1 complexes can be divided into two groups, canonical and variant, depending on their components. It is proposed that canonical complexes play a structural role in chromatin compaction, while variant complexes are responsible for sampling chromatin. I aim to determine the dynamics of PRC1 recruitment to chromatin at single molecule resolution. I will initially generate mouse embryonic stem cells (mESCs) expressing HaloTag fusion proteins exclusive to canonical and variant complexes, which can be labelled with cell permeable dyes allowing tracking of individual PRC1 molecules in live cells. Recruitment will be disrupted through mutation of specific components, or knockout or inhibition of processes depositing marks they recognise, with the aim of understanding the mechanism underpinning the dynamics of PRC1 recruitment. Generated cell lines will be used for both serum-to-2i transition and mESC differentiation to investigate how the dynamics of PRC1 recruitment change in development.

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

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

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that express a semi-invariant, MR1-restricted, T cell receptor (TCR). In humans, they comprise 1-10% of peripheral blood T cells and are enriched at mucosal sites. MAIT cells display characteristic expression of several surface molecules and transcription factors, and a typical cytokine response to stimulation. Therefore, they have been regarded as relatively homogeneous. However recent evidence indicates diversity in TCR expression and function that varies between tissues and individuals. Further investigation is required to understand the extent of MAIT cell heterogeneity and tissue-specific functionality. In several human autoimmune and inflammatory diseases, MAIT cells are activated or show phenotypic changes. How the altered cytokine environment in such diseases can modulate MAIT cell function remains to be determined. 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. 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. This will provide important insights into their physiological role both in health and 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

Understanding mechanisms that drive pain perception in early human development 11 Jul 2017

Pain in infancy has negative long-term consequences and its prevention is a clinical priority, but adequate treatment requires mechanistic understanding of the structural and functional development of human nociceptive circuitry. Recent scientific and technological advances provide insights into how noxious information is transmitted to the infant brain, providing a platform to ask how intrinsic brain network connectivity and the environment affect noxious-evoked brain activity, behaviour and ultimately pain perception in the developing infant nervous system. The fellowship goal is to understand the mechanisms that drive and modulate pain perception in early human development. I will ask whether inherent differences in how the brain behaves at rest influence variability in noxious-evoked activity, and will determine how this relationship is altered by environmental factors and pathology. I will establish how the development of structural and functional network connectivity alters noxious-evoked brain activity, and influences the dynamic relationship between brain activity and behaviour. I will translate this mechanistic understanding into clinical practice by conducting a clinical trial of an analgesic (fentanyl) during a minor surgical procedure, and will establish whether our newly-developed measures of noxious-evoked brain activity are suitable for use in infant analgesic dose-finding studies.

Amount: £60,000
Funder: The Wellcome Trust
Recipient: University of Oxford

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

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 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.

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

Decision-making by lymphocytes 11 Jul 2017

It was recognized sixty years ago that a "trigger mechanism" must initiate immune responses. Today, however, not even the broad features of the mechanism are fully agreed, despite its intrinsic scientific interest and the remarkable clinical utility of modulating lymphocyte behaviour. We do know, however, that it encompasses two separate events: receptor triggering per se, and the integration of multiple triggering outputs. Breakthrough developments in fluorescence imaging mean that we can now study molecular behaviour at cell-cell interfaces at single-molecule resolution, in real time. This means that we can directly test whether TCR triggering is explained by a theory relying on the local, physical exclusion of phosphatases from sites of receptor engagement and phosphorylation, called the kinetic-segregation model. We will explore how 'close-contact' formation affects the interplay of local signaling molecules, and test our theory using quantitative models of receptor signaling. We will also study the emergent properties of the types of modular networks known to mediate downstream signaling in T cells and, building on these findings, test a new, simple theory of signal integration. This programme of work will produce a fuller understanding of decision-making by lymphocytes, and a richer framework for thinking about immunotherapy.

Amount: £2,400,000
Funder: The Wellcome Trust
Recipient: University of Oxford

All-optical interrogation of neural circuits during behaviour 30 Sep 2017

Neural circuits display complex spatiotemporal patterns of activity on the millisecond timescale. Understanding how these activity patterns drive behaviour is a fundamental problem in neuroscience. To address this challenge, I have recently introduced a novel approach that combines simultaneous two-photon calcium imaging and two-photon targeted optogenetic photostimulation with the use of a spatial light modulator (SLM) to provide 'all-optical' readout and manipulation of the same neurons in vivo. I propose to probe the neural code in mouse barrel cortex during sensory-guided behavioural tasks by using this approach to uncover the underlying mechanisms of decoding and encoding of information by ensembles of neurons. I will train mice to make perceptual decisions based on quantitative control of cortical activity, as well as perturb neural activity in somatosensory cortex while animals are performing discrimination tasks using their whiskers. I can perform decisive tests of theoretical models describing the neural code by assessing the spatiotemporal pattern of activation required in somatosensory cortex to drive a behavioral response. These experiments will shed light on how many neurons with which functional signature are minimally sufficient to subserve a percept.

Amount: £25,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Mechanisms by which missense variants in myosin and myosin binding protein C alter cellular contractility in genetic cardiomyopathies. 19 Apr 2017

Summary: The cardiac sarcomere is a multi-protein complex essential to cardiac contractile function. Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are caused by pathogenic variants (PV) in sarcomere protein genes. Variants in genes directly involved in cellular contractility MYH7 (beta-myosin heavy chain), MYH6 (alpha-myosin heavy chain), and MYBPC3 (Myosin binding protein C) are either known or hypothesised to cause disease. Previous analyses of the mechanisms by which variants cause disease have relied on rodent models and extrapolation from clinical data. The introduction of clinically defined mutations into human iPSC-CMs using CRISPR/Cas-9 would allow the interrogation of these cellular phenotypes in a human background using molecular and mechanical strategies, adding clarity to the uncertainties of variant-phenotype relationships in these genes. Key goals: i) Interrogation of the molecular and biophysical (contraction and relaxation) mechanisms by which PVs in MYH7, MYH6, and MYBPC3 cause either HCM or DCM. ii) Define the contractile mechanism of MYH6 and MYH7 PVs to establish if they mirror one another. iii) Investigate if high throughput functional analyses of iPSC-CMs can be used to test individual variants of unknown clinical significance (VUS) to discriminate between those that are disease causing versus ‘benign’.

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

LipID: A Lipid Annotation Tool for Membrane Proteins 06 Jul 2017

Interactions of membrane proteins with lipids are important in their stability, regulation, and targeting. These interactions are of biomedical importance given the roles of membrane proteins in disease and as drug targets; with drugs often acting via lipid binding sites. We will develop a computational pipeline and database for molecular simulations to predict the structure, specificity, and affinity of membrane protein/lipid interactions. This will provide a unique 'computational biochemistry' resource for functional annotation of membrane protein structures, identifying potentially druggable sites. Building upon our MemProtMD methodology (http://sbcb.bioch.ox.ac.uk/memprotmd/), we will provide a server enabling simulation-based predictions of lipid binding sites to membrane protein structures, defining the structural basis of lipid interactions for each protein alongside predictions of lipid specificity and affinities. We have successfully established proof-of-principle methodologies which allow us to predict and explore free energy landscapes of membrane protein-lipid interactions. This technology needs methodological development to improve the accuracy, applicability, and robustness of predictions of lipid-protein interactions. We will develop a high-throughput software pipeline for lipid annotation of membrane proteins (LipID) for both known and new structures of two major groupings of membrane protein: (i) receptors, channels, and transporters from humans; and (ii) membrane proteins from pathogenic bacteria.

Amount: £719,367
Funder: The Wellcome Trust
Recipient: University of Oxford

Optogenetic analysis of the neural function of 5-HT-glutamate co-transmission 30 Sep 2017

This research investigates the relationship between 5-HT neurons and two key brain functions: sleep-wake changes and fear learning. Of particular interest is the role in these processes of glutamate co-released from 5-HT neurons. Two approaches will be used. One approach is based on recent evidence that glutamate is preferentially released from 5-HT neurons firing at low frequencies, whereas 5-HT is preferentially released at higher frequencies. The second approach is based on a mouse with glutamate deficient 5-HT neurons.In Oxford the research will have 3 main goals:i) Measurement of firing of identified 5-HT neurons during the sleep-wake cycle. This will be achieved using optotagging to record for the first time, the firing of identified 5-HT neurons during changes in sleep-wake activity.ii) Optogenetic manipulation of 5-HT neurons on sleep-wake activity. These experiments will optogenetically manipulate 5-HT neurons (using different stimulation frequencies) to establish the causal relationship between changes in 5-HT firing and sleep-wake activity.iii) Optogenetic manipulation of 5-HT neurons in mice with glutamate-deficient 5-HT neurons. These experiments will use a mouse with glutamate-deficient 5-HT neurons to further test the role of glutamate co-release.I will follow a similar research strategy to investigate the role of glutamate co-released from 5-HT neurons in emotional learning at NIH.

Amount: £80,000
Funder: The Wellcome Trust
Recipient: University of Oxford

A realist review of community engagement with health research 07 Dec 2017

The project will conduct a comprehensive review of community engagement using a realist review approach appropriate for tackling the conceptual complexity and practical diversity of the field. A review team with worldleading expertise in the theory and practice of CE will be supported by an advisory panel of internationally renowned realist review scholars. The review will begin with engagement with malaria research as a ‘pathfinder’ topic – and draw on a network of content experts, implementers and funders to input into and validate the review, ensuring its findings are widely disseminated and embedded in international CE work. Wellcome, BMFG and leading global health funders and implementation partners will benefit from a consolidated evidence base to underpin development of CE strategies in global health research and interventions. Outputs will include articles in peer reviewed open-access journals, an accessible evidence base on MESH/HELP, including context-relevant guidance for developing and evaluating CE strategies, and a critical mass of academics, practitioners, implementers and funders with a mutual interest in strengthening the theory and practice of engagement. In this way the review will spearhead the beginnings of a ‘science’ of community engagement and outline a clear value proposition for CE in global health research (14).

Amount: £260,250
Funder: The Wellcome Trust
Recipient: University of Oxford

Data sharing platforms to improve treatment outcomes in neglected tropical diseases 06 Jul 2017

We will develop data-sharing platforms to assimilate and collaboratively interrogate global data on i) schistosomiasis ii) soil transmitted helminths, iii) visceral leishmaniasis, iv) melioidosis and v) scrub typhus. This proposal will support the development of the technical platform and curation of data from tens of thousands of patients enrolled to treatment trials and programmatic data of these diseases for use in collaborative meta-analysis to answer key public health questions. The platform’s technical infrastructure will include secure data upload, auditable mapping of multi-disciplinary datasets to a standardised data structure, searchable data inventory and systems to request and receive data. The governance framework will ensure terms of data access that follow principles of equitable and ethical data sharing under the guidance of Science Advisory Committees nominated by the relevant disease communities. Support for the coordination and production of scientific output from the platform will be provided to ensure impact. Platform construction will leverage the expertise and investment in our existing malaria data platform, the WorldWide Antimalarial Resistance Network (WWARN). Prior funding has supported the development of successful pilot platforms for visceral leishmaniasis and schistosomiasis/soil-transmitted helminths, and we will assess the feasibility and impact of establishing platforms for melioidosis and scrub typhus.

Amount: £1,406,744
Funder: The Wellcome Trust
Recipient: University of Oxford

Modelling the impact of poor quality antimicrobials on patient outcome and drug resistance – a pilot study to inform policy in the absence of empirical data 30 Sep 2017

Antimicrobial resistance (AMR) is an increasingly serious and pressing global public health problem. Poor antimicrobial quality is increasingly realised as an important rectifiable impediment to global public health. There has been little discussion or evidence as to its comparative importance, in relation to other drivers such as poor prescribing and adherence, for both poor patient outcomes and AMR. In the absence of field data on the relationship between AMR and antimicrobial quality, mathematical modelling based on pharmacokinetic-pharmacodynamic relationships and rates of genetic change provides estimates which can be used to predict outcomes and inform policy. We propose a two phase modelling approach examining how poor quality essential medicines may affect patient outcomes and resistance selection and spread, modelling in Phase 1 antimalarials and in Phase 2 anti-tuberculosis and anti-hepatitis C medicines. This pilot project will build on the existing Wellcome investment in the Mahidol Oxford Research Unit (MORU) Network (though core funding) and the Infectious Diseases Data Observatory (through the MAPQAMP Biomedical Resources grant and core funding) for modelling, PK/PD and medicine quality resources and skills. The growing interest in medicine quality by nations and international organisations and the invitation by the WHO Member State Mechanism (on medicine quality) to the IDDO/MORU Medicine Quality Group to be a stakeholder, facilitates synergistic discussions with multiple partners and nations. We are also discussing expanding our collaboration with the United States Pharmacopeia PQM program on medicine quality & AMR. We are organising the first Conference on Medicine Quality & Public Health for September 2018 and we intend that the initial results from this work would be presented at this meeting. This project will therefore give the first objective evidence, rather than opinion, on the importance, or otherwise, of medicine quality on patient outcome and AMR, in comparison to poor adherence and poor prescribing. It will link in extremely well with the diverse activities of the MORU Network, IDDO, WHO, USP and diverse other stakeholders and be opportune for influencing policy for both medicine quality and AMR. This project will be linked to the parallel project proposed to Wellcome by Dr Elizabeth Pisani on ‘Understanding the political barriers to tackling sub-standard and falsified medicines’.

Amount: £99,994
Funder: The Wellcome Trust
Recipient: University of Oxford

Control of T cell responses by accessory receptors revealed by phenotypic models 11 Jul 2017

T cells orchestrate immune responses crucial for the elimination of infections and cancers. They do this by initiating a diverse set of effector responses when their T cell surface receptors (TCRs) recognise these threats. It is now appreciated that a large number of other, "accessory", receptors shape these responses. Indeed, the remarkable clinical success of checkpoint inhibitors and chimeric antigen receptors is based on perturbing accessory receptor signalling. Despite extensive research into the underlying biochemistry, we have yet to formulate canonical models of signalling that can predict how accessory receptors shape T cell responses. Here, we propose to use a mathematical method known as adaptive inference to identify signalling models directly from T cell response data, without prior biochemical assumptions. The method produces what we term phenotypic models because it coarse-grains over molecular information. These models provide effective pathway architectures showing how accessory receptors integrate (or not) with TCR signalling to shape response phenotypes. This will move the field beyond the current stimulatory/inhibitory binary paradigm of accessory receptors. The work offers a different way to study receptor regulated signalling pathways and the predictive power of the phenotypic model will be exploited for T cell-based therapies.

Amount: £1,783,754
Funder: The Wellcome Trust
Recipient: University of Oxford