Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Pulmonary arterial hypertension (PAH) is a cardiovascular disease that results from restricted blood flow through the pulmonary circulation, resulting in right heart failure. The symptoms of this disease include shortness of breath, dizziness, feeling faint and as it progresses, patients may have difficulty with everyday tasks such as climbing stairs. If left untreated, the prognosis is dismal, with a mean survival of 3-5 years. Despite advances in therapy in the last decade, current therapies are only modestly effective, which may be a reflection of our lack of understanding of the cause of the disease. A major breakthrough in the last decade was the identification of a single gene mutation that is responsible for up to 80% of cases of hereditary or familial PAH (HPAH), and about 25% of patients with sporadic idiopathic PAH (IPAH). The gene responsible is called the bone morphogenetic protein receptor-2 (BMPR2) gene, which encodes for protein receptor that is crucial to maintaining the integrity of endothelial cells (ECs) that line the vessels in the lung. Furthermore, ECs derived from patients with the BMPR2 mutation have shown a decreased ability to perform important functions such as repairing blood vessel networks. Using an approach known as proteomics, we have to surveyed global changes in proteins from ECs derived from patients with BMPR2 mutations. We are able to detect changes in a process known as phosphorylation, whereby phosphate groups are attached to proteins, is often a marker of increased activity. We intend to create a profile of phosphoproteins that are unique to BMPR2-mutant associated ECs and perform functional studies in cells and animals experiments to characterize whether these candidate proteins can be targeted as a therapy. We hope that a better understanding of BMPR2-associated HPAH will allow us to design early interventions aimed at preventing PAH in families with known mutations.