About the Project
Background: It is clear that inflammation underlies many important chronic disease states in both the central nervous system (CNS) e.g. multiple sclerosis and in the periphery e.g. modifying the pathogenesis of atherosclerosis and arthritis. My research group is interested in studying the endogenous pathways that regulate the magnitude and duration of the inflammatory response in order to discover new targets for the development of anti-inflammatory drugs.
Work leading up to the proposal: G protein-coupled receptors (GPCRs) play an important role in macrophage cell biology in disease processes including inflammatory cell recruitment and GPCRs are the target for many successful medicines. In recent work we identified a novel biased agonist at the immunometabolic receptor GPR84 (Lucy et al. 2019). We want to better understand the biology of other immunometabolic receptors by identifying novel chemical tool compounds and testing their effects on macrophages and microglia in inflammation.
Original hypothesis: We propose that novel small molecule agonists and cell metabolites active at immune-metabolic GPCRs will alter macrophage and microglial biological activity in inflammation. These biological activities such as chemotaxis, enhanced phagocytosis, changes in macrophage polarisation and secretion of cytokines could represent novel targets for the development of anti-inflammatory drugs.
Techniques to be used: The student will join a laboratory using a wide range of cell and molecular biology techniques with access to a wide range of pre-clinical models of human disease and a good track record in chemical biology and drug discovery and drug repositioning.
Funding Notes
4 Year DPhil Prize Studentships cover University fees, a tax free stipend of ~£17,009 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See https://www.path.ox.ac.uk/content/prospective-graduate-students for full details and to apply.
References
A Biased Agonist at Immunometabolic Receptor GPR84 Causes Distinct Functional Effects in Macrophages.
Lucy D, Purvis GSD, Zeboudj L, Chatzopoulou M, Recio C, Bataille CJR, Wynne GM, Greaves DR, Russell AJ.
ACS Chem Biol. 2019; 14(9): 2055-2064. doi: 10.1021/acschembio.9b00533.
The Impact of Cannabinoid Receptor 2 Deficiency on Neutrophil Recruitment and Inflammation.
Hussain MT, Greaves DR, Iqbal AJ.
DNA Cell Biol. 2019. doi: 10.1089/dna.2019.5024.
Efferocytosis perpetuates substance accumulation inside macrophage populations.
Ford HZ, Zeboudj L, Purvis GSD, Ten Bokum A, Zarebski AE, Bull JA, Byrne HM, Myerscough MR, Greaves DR.
Proc Biol Sci. 2019; 286(1904): 20190730. doi: 10.1098/rspb.2019.0730.
Cannabinoid receptor 2 deficiency exacerbates inflammation and neutrophil recruitment.
Kapellos TS, Taylor L, Feuerborn A, Valaris S, Hussain MT, Rainger GE, Greaves DR, Iqbal AJ.
FASEB J. 2019; 33(5):6154-6167. doi: 10.1096/fj.201802524R.
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