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Implementation of ISARICC's 2018-2022 Strategic Plan
<p>Bridging funds for transition to ISARICC's 2018-2022 Strategic Plan</p>
Development of compounds that inhibit RAS-effector protein-protein interactions in cancer using a single antibody domain drug surrogate emulator approach
Prof Rabbitts and colleagues from the Weatherall Institute of Molecular Biology have been awarded Seeding Drug Discovery funding to develop small molecules specifically targeting the RAS-effector protein-protein interactions. The RAS family of oncogenes is among the most frequently mutated in human cancers. Using minimal antibody fragments, the group has characterized an anti-RAS VH segment whos… more
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Wellcome Trust Clinical PhD Programme at the University of Oxford: a study of epigenetic changes in FOXP3 in regulatory T-cells and potential clinical application in allogeneic bone marrow transplantation.
The proposed research will study the influence of demethylating agents on the development and expansion of regulatory T-cells (Tregs). Tregs provide a crucial cellular mechanism of peripheral tolerance and are important in controlling Graft-versus-Host disease (GvHD). Their development is dependent upon the expression of the transcription factor, FOXP3. However, in humans, transient FOXP3 express… more
Wellcome Trust Clinical PhD Programme at the University of Oxford: gene therapy for multiple endocrine neoplasia type 1 (MEN1).
Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pancreatic islet, anterior pituitary and adrenocortical tumours for which effective treatments are not available. The MEN1 gene is located on chromosome 11q13 and encodes a 610 amino acid protein, MENIN. MENIN has functions in transcriptional regulation and genome … more
Wellcome Trust Clinical PhD Programme at the University of Oxford: Determining the role of Foxp3 regulatory T-cells in vivo.
Current understanding of the immune system has been radically influenced by the discovery of regulatory T-cells. No longer are aggressive and destructive immune cells thought to be the only players. There is more of an emphasis on the immune cells involved in policing immune responses and creating a state of tolerance to self antigens, so preventing autoimmunity. Regulatory T-cells (T-Reg cells… more
Development of thalamocortial connections in mouse barrel cortex: Role of subplate neurons.
The overall aim is to understand the development of synaptic interactions in the early thalamus-subplate-layer 4 microcircuit of mouse barrel cortex. Two specific objectives have been identified: 1. To determine the developmental profile of synaptic function at three identified synapses within this microcircuit during early postnatal development, and 2. To test the hypothesis that spike timing-dependent plasticity can explain the developmental changes at these three synapses.
The molecular cell biology of the Leishmania parasite / host macrophage interface.
The molecular cell biology of the Leishmania parasite I host macrophage interface. Our overall objective is to define the cell biological processes contributing to the Leishmania parasite's success in growing within a parasitophorus vacuole in the host macrophage. We will focus specifically on the role of the short, immotile flagellum which we postulate to have a sensory role. Specific Aims 1. To… more
Identification of the molecular mechanisms of Il-23-driven intestinal inflammation.
Maintenance of the integrity of the gastrointestinal tract requires a delicate balance between proinflammatory T effector cell responses directed at pathogenic organisms and anti-inflammatory T regulatory cell (Treg) responses toward the commensal flora . In individuals suffering from inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, this balanced intestinal im… more
A SYSTEMATIC APPROACH TOWARDS UNDERSTANDING INNATE IMMUNITY AGAINST TRYPANOSOMES.
The project aims to provide a cellular and molecular view of innate immunity against trypanosomes. Despite recent findings a detailed structural explanation of the events occurring at the molecular and cellular level is missing. Specifically, inter-related and complementary aims are to: (1) Follow the morphologically distinct stages from uptake of the lytic factor to trypanosome cell death by ge… more
Reducing childhood mortality in the tropics. Development of a combined antimalarial-antibacterial rectal formulation for community use.
Summary not available
The structural basis of the binding specificity of the family of SIRP paired receptors.
The structural basis of the SIRP family of receptors will be determined. (i) X-ray crystallography will be carried out on the ligand binding domains of the SIRP beta and gamma (SIRP alpha has already been completed) (ii) The structure of the complex between CD47 and SIRPalpha will be determined working on extensive preliminary data. (iii) The structure of the three extracellular domains of SIRP a… more
Cryo-electron microscopy of pathogens and receptor complexes.
The program will use cryo-electron microscopy and three-dimension reconstruction to study pathogenic viruses and the effects of infection on cells. Much of the microscopy will be conducted under P3 conditions and is associated with the establishment of a Facility for the Examination of Infectious Particles in Oxford which will include contained high end cryo-microscopes. The topics explored will … more
Genetic control of cell fate decisions in the devloping mouse embryo.
We are studying the complex cellular interactions underlying early mammalian development, and in particular the signals provided by members of the TGFß superfamily of secreted growth factors. We have previously shown that nodal activity is required for primitive streak formation and anterior patterning during gastrulation, and at later stages for establishment of the L/R body axis. We also descri… more
The impact of vaccine platform on the cellular drivers of humoral immunity
<p>The focus of this Fellowship proposal is on how vaccine platform affects the cellular drivers of humoral immunity, specifically memory B cells (mBCs) and T follicular helper (Tfh) cells. I will compare the leading <em>Plasmodium falciparum</em> blood-stage malaria candidate – RH5 – in two vaccine platforms: heterologous viral vectors (chimp adenovirus 63 prime, Modified Vaccinia An… more
The Ethics of Genome Editing in Livestock
<p>Genome editing in livestock (GEL) could potentially be used to mitigate urgent global problems of infectious disease, antimicrobial resistance, global warming, and animal suffering while also increasing agricultural productivity. Despite its imminence and potentially transformative potential, there has been minimal ethical debate about GEL. This project will provide the first in-depth philosop… more
The role of diurnal intracellular chloride changes in cortical network activity and plasticity.
<p>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 di… more
A realist review of community engagement with health research
<p>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 engagemen… more
Overcoming contraceptive discontinuation by overcoming side-effects: paving the way for personalized contraception in Ethiopia
<p>In the developing world, millions of women discontinue hormonal contraception due to the experience of debilitating physiological side-effects (e.g. excessive and irregular bleeding), yet the causes of these adverse effects is not known. This project will be the first to test the hypothesis that side-effects are caused by unnecessarily high dosage of exogenous hormones in hormonal contraceptiv… more
Exploring mechanisms of enhancer action in erythropoiesis
<p>DNA sequences called enhancers control gene expression in time and space by activating genes during key cell-fate decisions. The specific combinations of genes activated by enhancers contribute to cellular behaviour, genetic predisposition to disease and phenotypic variation between species. My aim is to understand precisely <em>how</em> enhancers activate genes during differentiation.</p> <p… more