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Recipients:
University of Oxford

Results

Design and evaluation of a modified vaccinia Ankara vector therapeutic vaccine for hepatitis B immunotherapy 30 Sep 2018

Hepatitis B virus (HBV) is a serious global health problem, with approximately 240 million people chronically infected. Long-term infection can lead liver failure, cancer and death. Current therapy controls but does not eradicate the infection. T cells are a type of immune cell necessary to fight HBV. During chronic hepatitis B these cells become less active. Checkpoint inhibitors are a form of immunotherapy that enables T cells to function again. In a study of woodchucks infected with a similar virus to HBV, treatment with vaccine and checkpoint inhibitor lead to better control of the virus. This project aims to use this combination of vaccine and checkpoint inhibitor, to treat patients with chronic HBV. A vaccine using a virus to carry the HBV proteins has been developed and shown to generate good immune responses in mice. We plan to develop a second vaccine to boost this response and test the vaccines together with checkpoint inhibitors in mice infected with the HBV virus. This will allow us to assess how effective this is at eradicating HBV. If the results from this study are promising, this could pave the way for clinical trials in humans with chronic HBV.

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

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through a multidisciplinary and hypothesis-driven programme of research that builds on a series of exciting new and unpublished observations to discover how CGIs function to activate(Aim1) and maintain(Aim2) transcription, and test whether CGIs create gene expression switches(Aim3).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

Dissociation: Developing a Cognitive Maintenance Model and Psychological Intervention 30 Sep 2018

As we interact with the world around us, our experience is a result of the synthesis of our consciousness, memory, sense of identity and perception. In ‘dissociation’, this coherence fails or disintegrates. The disintegration may be sudden – meaning that people experience sudden ‘black-outs’ and amnesia for the intervening time – or gradual, where the person may feel increasingly numb or detached from reality. Chronic dissociation is an important problem for mental health professionals to address because it can cause considerable distress and disruption. It is the strongest predictor of a person making multiple suicide attempts, and is thought to underlie self-harming behaviour (such as ‘cutting’). Dissociation is not just experienced in ‘dissociative disorders’, but also across many different psychiatric disorders, including up to 50% of people with psychosis. The aim of this project is to develop and test a new psychological explanation of dissociation as it occurs in psychosis. First, experiments will be carried out with members of the general population to determine which psychological factors perpetuate dissociative experiences. Then, a psychological treatment which targets one or more of these factors will be developed and tested with a small group of people with psychosis and dissociation.

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

Autophagy in the interplay between haematopoiesis and the bone marrow niche 30 Sep 2018

Autophagy (greek ‘self-eating’) is a cellular recycling process, which can provide new building blocks and energy to cells. Immune cells require autophagy for their differentiation, maintenance and function. Hence, decreased autophagic flux, which occurs naturally during aging, results in diminished immune function. The effect of autophagy in immune cells is particularly apparent in immune cells that permanently live or are generated in the bone marrow (BM). We aim to understand how autophagy regulates the interplay of immune cells and the BM environment. First, we aim to deplete autophagy in hematopoietic stem cells using genetic models and assess the effects on supporting cells in the bone marrow. For this we will use global and bioinformatic tools to study the BM composition based on both, gene expression and metabolite production. Second, we aim to deplete autophagy from bone marrow adipocytes, a subset of cells known to be able to provide building blocks and metabolites such as fatty acids to surrounding cells. We will study normal hematopoiesis and long-lived immune responses in this new mouse model. Findings from this project will be key to identify better conditions for hematopoietic stem cell transplantations and counteract negative effects of aging including inflammation.

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

Wnt secretion, trafficking and pathway activation: towards a structure-based understanding 30 Sep 2018

In recent years of cancer research, significant focus has been dedicated to the definition of the so-called "hallmarks of cancer", i.e. common alterations underlying and unifying the apparent diversity of this extremely multifaceted, complex and heterogeneous disease. A recurrent theme identified both in early setting of tumour initiation - particularly in relation with maintenance of cancer stem cells - as well as in advanced and metastatic settings, relates to alterations in the Wnt pathway. This is a pivotal signalling way controlling growth and body organization in the embryo; in the adult life, it governs tissue regeneration and homeostasis in a tightly regulated manner. My aim is to investigate the events involved in the activation phase of the signalling cascade, with a special attention to the mechanisms of secretion and extracellular trafficking of the activating ligand (the Wnt protein itself). I will do that using the tools of structural biology, in particular x-ray crystallography and, where applicable, cryo-EM. Coupled with a detailed functional analysis based on the structural findings, the work will help shedding light on a so-far unclear molecular picture, in turn enhancing the options for a targeted modulation of the pathway for therapeutic purposes.

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

Molecular Simulations of Membrane Protein Lipid Interactions 31 May 2018

Membrane proteins account for ca. 20% of all genes, 40% of drug targets, and are mutated in many human diseases. The past decade has witnessed an exponential rise in the number of high resolution membrane protein structures. Interactions with lipids are of crucial importance for the stability, regulation, and targeting of membrane proteins, but structural and biophysical data on membrane protein-lipid interactions remain sparse. Molecular dynamics (MD) simulations provide a key tool for probing the interactions of lipids with membrane proteins. The overall aim is to apply multiscale simulations to predict specific lipid interactions of lipids with recently determined cryoEM structures of selected membrane proteins. This will be achieved by a serial multiscale approach. Coarse-grained simulations will be used to identify the interaction of membrane proteins with the lipids of complex membranes (i.e. in physiologically relevant mixed lipid bilayers based on lipidomics data). Atomistic simulations will be used to refine the resultant models. Predictions of protein/lipid interactions will be tested experimentally via our collaborators.

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

Understanding unconventional kinetoplastid kinetochores in Trypanosoma brucei 10 Apr 2018

I am interested in understanding the mechanism of how eukaryotic cells inherit their genetic material at each round of cell division. I have been studying the kinetochore, the macromolecular protein complex that drives chromosome segregation. Although it was widely believed that the structural core of kinetochores would be composed of proteins that are conserved in all eukaryotes, I discovered an unconventional class of kinetochore proteins (KKT1–20) in Trypanosoma brucei, an evolutionarily-divergent kinetoplastid parasite. My current goal is to understand how they carry out conserved kinetochore functions such as binding to DNA and microtubules. Based on preliminary data, I propose that two homologous protein kinases KKT2 and KKT3 lie at the base of the kinetoplastid kinetochore. I will aim to understand how these proteins localize specifically at the centromeric DNA using a variety of approaches. I will also characterize the KKT4 protein to reveal the mechanism of microtubule interaction. To understand the design principle of kinetoplastid kinetochores, I will reconstitute and characterize kinetochore subcomplexes. Finally, I will examine how the evolutionarily-conserved Aurora B kinase regulates the function of unconventional kinetoplastid kinetochores.

Amount: £1,890,493
Funder: The Wellcome Trust
Recipient: University of Oxford

An exploration of the role L-type calcium channels in mood, cognition and sleep. 30 Sep 2018

I plan to explore the effect of nicardipine, a brain-penetrant calcium channel antagonist, on mood instability and its cognitive/neural correlates. This research (carried out within the Collaborative Oxford Network for Bipolar Research to Improve Outcomes [CONBRIO]) has a number of goals. In addition to studying effects of L-type calcium channel (LTCC) antagonism on mood instability, I will investigate effects on sleep/cognition, and on brain activity measured by functional imaging. Rationale is provided by (a) considerable evidence for calcium signalling abnormalities in bipolar, (b) current mood stabilisers correct some of these abnormalities, (c) calcium channel genes contribute to the basis of bipolar as well as to memory/sleep. Moreover, LTCC antagonists are used for heart disease and available for experimental studies; there have also been early studies in bipolar disorder but no robust results. I will study volunteers screened for high mood instability and risk CACNA1C genotype, and assess mood, sleep, cognition, and neural activity, before and after randomisation to nicardipine or placebo. Results will inform whether trials of LTCC antagonists for bipolar disorder are indicated, and their likely efficacy/tolerability. I will learn to conduct a randomised trial, principles of experimental medicine, and aspects of cognition, circadian-biology, and functional brain imaging.

Amount: £0
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

open access award 2017/18 30 Sep 2018

Not available

Amount: £85,000
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

MAXIMIZING THE KNOWLEDGE GAINED FROM CALIFORNIA SENATE BILL 27 30 Sep 2018

On January 1, 2018, California enacted Senate Bill 27 (SB27), first-of-its-kind and potentially precedent-setting legislation, which will require a veterinarian’s prescription for use of antimicrobial drugs and ban non-therapeutic antimicrobial uses for routine disease prevention and growth promotion in livestock. To assess the effectiveness of this important legislation at reducing antimicrobial resistant bacterial infections in humans, we propose the following specific aims: Aim 1. Quantify the effect of SB27 on E. coli, Campylobacter and Salmonella resistance rates from retail meat. Aim 2. Estimate the proportion of human Campylobacter, Salmonella, and extraintestinal pathogenic E. coli infections caused by strains of food-animal origin in California. Aim 3. Characterize the effect of SB27 on the antimicrobial susceptibility of Campylobacter, Salmonella, and extraintestinal E. coli infections caused by strains of food-animal origin in California. Implementation of SB27 provides a unique natural experiment to assess the effectiveness of restrictive agricultural antimicrobial-use policies at reducing antimicrobial-resistant human infections. The proposed research will have a positive impact by prospectively measuring the effect of this policy on the antimicrobial susceptibility of E. coli (an important colonizing opportunistic pathogen) and Campylobacter and Salmonella (two frank foodborne pathogens) and thereby maximizing the information gained from this singular opportunity

Amount: £254,330
Funder: The Wellcome Trust
Recipient: University of Oxford

Role of FoxP heterodimers in perceptual decision-making 31 May 2018

The role of the transcription factor FoxP (Forkhead box P) during perceptual decision-making tasks will be investigated in alpha-beta core Kenyon cells, the main neural component of mushroom bodies in fruit flies (Drosophila melanogaster). FoxP plays a role in evidence accumulation via repression of the dendritic KV channel Shal in alpha-beta core Kenyon cells. A yeast two-hybrid screen followed by co-immonoprecipation studies has elucidated that FoxP exerts its repressive as a heterodimer with two potential partners, the transcription factors ATF-6 and GCM. My research will focus on a functional characterisation of FoxP heterodimers in decision-making. I will use NP6024-GAL4 to express RNAi transgenes against candidate transcription factors (ATF-6 and GCM) in Drosophila alpha-beta core Kenyon cells and measure the flies' reaction times and decision accuracies relative to both parental controls, FoxP5-SZ-3955 mutants, and flies expressing NP6024-GAL4-driven FoxPRNAi. I expect to find similar reaction time phenotypes in experimental flies with ATF-6/GCM knockdown as in FoxP mutants or FoxPRNAi flies. This would indicate that FoxP exerts its main repressive function on the Shal promoter by interacting as a heterodimer with either ATF-6 or GC).

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

In Their Own Voices: Vulnerabilities & Abilities of Women, Children, & Families in Health Research 05 Apr 2018

As REACH enters its second year, we have an exciting opportunity to use our early findings and to expand our use of visual methods to spark wider community and public debate about the ethical issues arising in research with women, children and their families in contexts of poverty and gender inequality. This proposal complements existing Africa and Asia Programme provisions for public engagement at the KEMRI-Wellcome Trust Research Programme, Africa Health Research Institute and the Mahidol Oxford Tropical Medicine Research Unit. We propose a linked series of public engagement workshops and events across our four study countries, to engage with members of the general public, community activists, humanitarian health workers, programme leaders in women’s and children’s health, and community advisory boards. Using cases and videos to prompt lively debate and discussion, we hope to learn from participants about what ethical research means to them, what vulnerability and empowerment mean to them, potential concerns about research, and ideas for responding to these concerns. Participatory workshops will be filmed and an edited video created to share public insights with researchers, universities, funders, ethics committees, and other stakeholders in global health. These activities will: Offer an opportunity for public stakeholders to shape the debate around research ethics in their communities and beyond. Increase public awareness and elicit public insights about the role for ethical research in evidence-based responses to health and social needs in contexts of poverty and gender inequality. Offer public engagement training and practice for developing country researchers in research ethics.

Amount: £140,079
Funder: The Wellcome Trust
Recipient: University of Oxford

Signal transduction of the GPCR Smoothened: a key protein in Hedgehog-regulated morphogenesis and oncogenesis 30 Sep 2018

In complex multicellular organisms, cell-to-cell communication is often managed by morphogen gradients. The secreted Hedgehog ligands fall within this class, as they act in this manner during embryonic development. The Hedgehog signalling pathway (stimulated by these morphogens) tightly regulates crucial developmental processes including body patterning and symmetry. Serious developmental disorders result from inactivation of this pathway during embryogenesis, including holoprosencephaly and cyclopia. Hedgehog signalling is also active through stem cell programs throughout adult life, and aberrant Hedgehog activation, either ligand dependent or mutations in pathway components, can lead to cancer including medulloblastoma and basal cell carcinoma. The G-protein coupled receptor (GPCR) Smoothened is a key protein of this pathway, as it initiates the intracellular cascade, and is already targeted by anti-cancer drugs including Vismodegib and Sonidegib. However, the mechanism of signal transduction has only been poorly characterised. This project aims to explore this using both structural and biophysical approaches. We will study the mechanism and interplay of the two identified ligand-binding sites and the dynamics of agonist association with Smoothened. The ultimate goal is to determine the structure of active-state Smoothened and hence describe the mechanism by which its signal is transmitted across the plasma membrane.

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

Malaria exposure, emergency care and severe disease phenotypes in African children 07 Jul 2018

Malaria continues to pose a huge burden on African communities and hospitals. Despite scaled mosquito vector control coverage, many children across the central belt of Africa continue to be infected with the malaria parasite every year. Despite improved access to effective malaria medicines and diagnostics, malaria remains the leading cause of admission to paediatric wards at many hospitals, with children often admitted with life-threatening illness. New evidence is required to understand the relationship between rates of infection exposure and severe malaria in childhood and how these children reach emergency services. I propose to use a network of hospitals in Africa, to answer two related questions: a) how does the incidence and phenotype of severe malaria vary between malaria ecologies, at a time of increased control coverage? and b) what are the pathways to hospitalization with severe malaria? This work is intended to improve our ability to predict impacts of current and new tools aimed at reducing parasite exposure, identify points of improved referral care and demonstrate how upgraded hospital data can be used as epidemiological surveillance instruments to measure impacts of community-based control.

Amount: £2,428,260
Funder: The Wellcome Trust
Recipient: University of Oxford

The organisation of international cooperation in relation to AMR 30 Sep 2018

The world has agreed to take action on Antimicrobial Resistance (AMR). The UN General Assembly Resolution on AMR commits UN Member States to addressing AMR therefore they called for the establishment of an ad hoc Inter- Agency Coordination Group (IACG). Equally importantly, both health and agriculture sectors are being brought together to address this problem. with the UN Secretary General in consultation with the WHO, the UN FAO and the OIE establishing this multidisciplinary group composed of 13 UN organisations and 13 independent experts. The IACG is mandated to report on progress and recommendations for the next steps to ensure sustained effective global action. The global governance mechanisms to deliver on an AMR strategy are crucial. Without some global coordination, none of the public or private stakeholders in this issue will move very far. To this end, as part of IACG's work an analysis of existing governance mechanisms is required by March/ April 2018 to inform the discussion on possible future governance mechanisms for AMR. The paper we are proposing will undertake these analyses and lay out how international cooperation could best be organized to manage the urgent problems emerging from AMR.

Amount: £51,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural Biology of Membrane Proteins in Diseases of Aging 30 Sep 2018

Solving the 3D molecular structure of membrane proteins has historically been difficult, but recent technological advances have made many more membrane proteins viable targets. Membrane transporters and ion channels are important in all cells, but are particularly important in the nervous system. This project aims to solve a 3D membrane protein structure using either cryo-electron microscopy or x-ray crystallography, beginning with a set of candidate proteins involved in disease or vital function. These include: ABCC5, a Type 2 diabetes associated protein and transporter of the neurotransmitter glutamate in the brain; ABCA7, an Alzheimer’s disease associated protein, which transports lipids; HCN2, an ion channel associated with neuropathic pain and the CNGs, a family of proteins which form heteromeric ion channels found in the retina and olfactory system. We plan to complement the structural study with activity assays of purified protein in combination with known substrates and modulators.

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

Serine ADP-ribosylation in genome stability and human disease 10 Apr 2018

ADP-ribosylation (ADPr) is a post-translational modification (PTM) of proteins, synthesised by the poly(ADP-ribose) polymerase (PARP) family of enzymes. Through the modification of a variety of mediator/effector proteins, PARPs control cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the proteins involved in these pathways and their mechanisms of regulation remain poorly understood. Recently, we identified ADPr on serine residues in proteins (Ser-ADPr) as a previously unknown PTM. We showed that Ser-ADPr synthesis is dependent on histone PARylation factor 1 (HPF1), a recently identified specificity factor and interactor of DNA repair PARPs - PARP1 and PARP2. We further showed that Ser-ADPr specifically targets proteins involved in the maintenance of genome stability. Finally, we also revealed that a hydrolase called ARH3 acts as specific enzyme for a timely reversal of Ser-ADPr. Our first goal of this project is to use biochemical and structural approaches to understand the exact molecular mechanism by which HPF1 and ARH3 work in the synthesis/removal of Ser-ADPr. Our second goal is to define the physiological processes controlled by Ser-ADPr and to understand how these processes are regulated in cells, using cell biology approaches and animal models.

Amount: £2,074,702
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural Characterisation of the Orthobunyaviral Surface Glycoproteins 30 Sep 2018

Orthobunyaviruses present medical and economical threats as they cause haemorrhagic fever and encephalitis in human, and abortion and stillbirth in livestock. Currently, little is known about how orthobunyaviruses infect their hosts and how they achieve cross-species transmission from anthropods to humans. My DPhil research focuses on structurally characterising the glycoproteins utilised by the orthobunyaviruses for infection and screening for neutralising antibodies. Using X-ray crystallography and electron microscopy techniques, I aim to contribute to a more complete understanding of orthobunyavirus-host cell attachment, intracellular trafficking, and membrane fusion. Ultimately, knowledge of host-cell entry mechanism will aid the development of vaccines and inhibitive peptides.

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