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Title: Identification and characterisation of a putative osteoprotegerin receptor on pulmonary arterial smooth muscle cells
Author: Dawson, Sarah Helen
ISNI:       0000 0004 5357 8367
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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Pulmonary arterial hypertension (PAH) is a rare but fatal lung disease with a high mortality. Pathologically, PAH is characterised by progressive pulmonary vascular remodelling and it is well known that pulmonary arterial smooth muscle cell (PASMC) proliferation and migration is a key driver of this remodelling. Recently, the secreted glycoprotein, osteoprotegerin (OPG) has been implicated as an important pathogenic mediator in PAH. OPG is elevated within the serum and pulmonary vascular lesions from patients with PAH and OPG induces PA-SMC proliferation and migration in vitro. Furthermore, genetic deletion or antibody blockade of OPG can prevent and reverse established disease in pre-clinical animal models of PAH. However, it remains unclear how OPG signals to induce PA-SMC proliferation. Therefore, the work undertaken in this thesis aimed to characterise the OPG signalling cascade in PA-SMCs and identify the receptor through which this is mediated. OPG was found to induce significant expression of CDK5, phospho-CDK4, phosphoERK1/2, phospho-HSP27 and significantly altered expression of phospho-mTOR in PA-SMCs. OPG significantly altered the expression of 57 PAH-associated genes in PA-SMCs. Investigations into identifying an OPG binding partner revealed four novel interactions between OPG and Fas, IL1RAcP, GAP43 and TMPRSS11D. The interaction between OPG and Fas was confirmed in PA-SMCs. Fas expression was elevated in PA-SMCs, the pulmonary artery and right ventricle from idiopathic PAH patients. Fas blockade significantly inhibited OPG-induced gene expression in PASMCs and significantly inhibited OPG-induced PA-SMC proliferation by 34%, which was further reduced by simultaneous TRAIL blockade. These data begin to reveal the receptor and novel intracellular signalling mechanisms through which OPG induces PA-SMC proliferation. As well as further highlighting OPG as a potential therapeutic target in PAH, these data also suggest a more diverse role for OPG in other biological systems.
Supervisor: Lawrie, Allan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available