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Identifying inhibitors specific to the OPG-kinome: towards novel treatments for Pulmonary Arterial Hypertension (PAH).


Project Description

Background: Pulmonary arterial hypertension (PAH) is a fatal progressive disease. Median life expectancy in untreated PAH patients is 2.8 years. 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 (plexiform) lesions. Current drugs target vasoconstriction via the prostacyclin, endothelin or nitric oxide pathways often in combination. However, current treatments do little to address the underlying proliferative vascular disease.

Osteoprotegerin (OPG, TNFRSF11B) is a basic glycoprotein secreted as either a monomer or multimer by cells of the heart, lung, vasculature and immune systems. OPG is a mitogen to both PA-EC and PASMC and 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.

Objectives: We now aim to determine the OPG-Fas 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.
Novelty: There are no small molecule inhibitors of this pathway.
Timeliness: New drug targets and treatment strategies are urgently needed for PAH.
Experimental Approach: Using cells obtained through collaboration with colleagues in the UK, Germany, US and Canada, the successful candidate will profile the kinome for 20 lines of Ctrl-PASMC and 20 lines of PAH-PASMC +/- OPG using the PamGene platform (https://www.pamgene.com/) to profile 144 tyrosine and 144 serine/theronine kinases. This will define the OPG kinome in Ctrl vs PAH PASMC and determine if there are effects of FAS neutralisation independent of OPG (FAS mAb vs OPG mAb vs IgG4). These data will provide important comparative insights into the signalling response in Ctrl- and PAH-PASMC and provide critical information on the effect of blocking this pathway at the ligand and receptor level. 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).

Funding Notes

This project is open to self-funded students only.

Entry Requirements:
Candidates must have a first or upper second class honors degree or significant research experience.

References

Enquiries:
Interested candidates should in the first instance contact Prof Allan Lawrie, [email protected]

How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select “Infection, Immunity and Cardiovascular Disease” as the department.

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