Joshua Hodgson

Supervisor: Prof Nick Morrell

Title: Bone morphogenetic protein 9 (BMP9) in pulmonary arterial hypertension

Abstract: Pulmonary arterial hypertension (PAH) is a rare disease, caused by dysfunction of cells lining pulmonary arteries. Blocked and narrowed vessels increase strain on the right heart, which dilates, and eventually fails. For those diagnosed with PAH, prognosis and treatment options are poor.

Whilst the majority of familial PAH cases are associated with mutations to the type 2 bone morphogenetic protein receptor gene, BMPR2, genetic contributors to idiopathic and other PAH cases are not well known. Multiple lines of evidence implicate BMP9, which signals through BMPR-II, including the fact that this group has shown BMP9 administration can reverse symptoms and dysfunctions of PAH in mouse and rat models. Therefore, BMP9 is extremely interesting as a potential therapy for PAH, but much of its biology is unknown.

My project will investigate the functionality of BMP9 variants, which have been found by this lab in the whole genome sequences of PAH patients. The pharmacokinetics of BMP9 will be studied, for the first time, in mice. The mechanisms through which BMP9 exerts its effects will be analysed through different assays, including RNA sequencing of wild-type and BMPR2 mutant cells. Finally, the effect of genetic BMP9 impairments will be studied in mice pre-disposed to developing PAH like symptoms.