Pulmonary arterial hypertension (PAH) is a fatal progressive disease with a median life expectancy of 2.8 years, untreated. Pathologically, PAH is characterised by sustained pulmonary vasoconstriction and progressive obliteration of resistance pulmonary arteries and arterioles caused by medial thickening, intimal fibrosis and formation of angioproliferative lesions due to unchecked cellular proliferation and recruitment. Current drugs target vasoconstriction via the prostacyclin, endothelin or nitric oxide pathways often in combination but do little to address the underlying proliferative vascular disease.
We have identified that the protein osteoprotegerin (OPG, TNFRSF11B) is a mitogen to both PA-EC and PASMC, and that levels are increased in patients with, and animal models of PAH. In rodents, genetic deletion or inhibition of OPG prevents and reverses development of PAH. We have identified and validated a new receptor for OPG on PASMC, Fas (TNFRSF6) and have demonstrated that knock-down of Fas in vitro prevents OPG-induced proliferation and migration of human PASMCs.
New drug targets and treatment strategies are urgently needed for PAH. We are currently exploring the translation of a novel anti-OPG antibody to the clinic. There are no small molecule inhibitors specifically designed to target this pathway, and it is no known whether any existing drugs influence this newly discovered ligand-receptor signalling.
We now aim to define the downstream OPG-Fas signalling cascade (kinome) in cells isolated from patients with PAH, and map with known kinase inhibitor profiles to identify candidate drugs that will suppress vascular cell proliferation in both in vitro and in vivo models of PAH. The candidate will use primary cells obtained through collaboration with colleagues in the UK, Germany, US and Canada to profile the kinome for 20 lines of Ctrl-PASMC and 20 lines of PAH-PASMC +/- OPG stimulation using the PamGene platform (https://www.pamgene.com/
) to profile 144 tyrosine and 144 serine/theronine kinases. This will be performed in collaboration with colleagues at the University of Giessen, Germany and define the OPG kinome in ‘diseased’ PASMC compared to control. The candidate will then determine the effect of blocking this at both the receptor (FAS) and ligand (OPG) level (FAS mAb vs OPG mAb vs IgG4). This will identify known targets for current kinase inhibitors that will prioritise kinase inhibitors to test in vitro on ctrl and PAH-PASMC assays for proliferation, migration and apoptosis. Inhibitors with supportive in vitro data will then be assessed therapeutically in in vivo models of PAH (e.g. Sugen5416 plus hypoxia in mouse and rat) providing a broad spectrum of training opportunity in both in vitro and in vivo models of pulmonary vascular disease.
Supervisor: Dr. Allan Lawrie: https://www.sheffield.ac.uk/iicd/profiles/lawrie
The Donald Heath research programme in Pulmonary Hypertension: http://www.donaldheath.org
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