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dc.contributor.authorRavindran, Dhanya
dc.date.accessioned2019-10-01
dc.date.available2019-10-01
dc.date.issued2019-02-28
dc.identifier.urihttp://hdl.handle.net/2123/21163
dc.description.abstractInflammation is a central process in the pathophysiology of cardiovascular diseases (CVD) that involves the coordination of pro- and anti-inflammatory molecules to control tissue damage against pathogenic injury. Chemokines have been recognised as key elements in modulating specific intracellular signalling pathways in the regulation of critical inflammatory processes including leukocyte recruitment to sites of tissue damage, a fundamental immune response in the initiation of an inflammatory cascade which is essential for its resolution. Chemokine-mediated endothelial and smooth muscle processes are largely implicated in inflammation-driven pathological conditions such as atherosclerosis and injury-induced excessive neovessel formation. Identifying an inhibitor capable of targeting specific chemokines involved in inflammation while maintaining essential physiological processes required for tissue repair is important for providing a rational therapeutic strategy. One such broad-spectrum chemokine inhibitor is the ‘M3’ protein, encoded by the murine gammaherpesvirus 68 (MHV-68). M3 binds a broad spectrum of chemokines with high affinity, with specificity to pro-inflammatory chemokines including CCL2, CCL5 and CX3CL1. To date, the effect of broad-spectrum chemokine inhibition has not been described in the context of atherosclerosis or pathophysiological angiogenic processes underpinning cardiovascular events. This thesis aimed to elucidate the role of broad-spectrum chemokine inhibition using M3 protein under physiological and pathological conditions in vivo using an ischaemia-mediated model of femoral artery ligation, and inflammation-driven models of atherosclerosis and vascular injury. This thesis also aimed to replicate these models in vitro using human endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) under inflammatory or hypoxic conditions, induced with macrophage-conditioned media (MCM) or 1% O2 respectively. The major findings of this thesis were first, M3 protein suppressed chemokine receptor-directed cell migration in vitro. In addition, chemotaxis assay using mouse plasma revealed that M3 reduced activity of circulating inflammatory chemokines CCL2, CCL5 and CX3CL1, but not the homeostatic chemokine CXCL12. Second, M3 suppressed inflammation-driven atherosclerosis progression in vivo, and this was found to be more effective in a slower rate of atherosclerosis which is more representative of plaque development in people. Third, M3 attenuated inflammatory-driven angiogenesis in response to perivascular cuff injury, and suppressed cuff-induced intimal thickening by modulating chemokine-mediated VSMC activation. Importantly, M3 preserved essential physiological angiogenesis, arteriogenesis and had no effect on blood perfusion in a model of ischaemic injury. Finally, these effects in key cellular processes were recapitulated in vitro in ECs and VSMCs under inflammatory and hypoxia conditions in functional assays. This thesis provided proof of concept for the potent anti-inflammatory effects mediated by broad-spectrum chemokine inhibition using M3 chemokine-binding protein and demonstrated that there is promise for an immunomodulatory role in the treatment of inflammatory-driven vascular diseases associated with CVD.en_AU
dc.publisherUniversity of Sydneyen_AU
dc.publisherFaculty of Medicine and Healthen_AU
dc.publisherHeart Research Instituteen_AU
dc.rightsThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
dc.subjectAngiogenesisen_AU
dc.subjectatherosclerosisen_AU
dc.subjectchemokineen_AU
dc.subjectinflammaionen_AU
dc.titleThe Role of Broad-spectrum Chemokine Inhibition in Vascular Diseasesen_AU
dc.typePhD Doctorateen_AU
dc.type.pubtypeDoctor of Philosophy Ph.D.en_AU
dc.description.disclaimerAccess is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.en_AU


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