Grant: Doctoral: Vanier Canada Graduate Scholarships

Pulmonary arterial hypertension (PAH) is disease characterized by abnormally high blood pressure in the vessels of the lungs as well as severe narrowing and scarring in these arteries. It is a chronic, debilitating disease that, if left untreated, can progress to heart failure and eventually death. Unfortunately, there is no medical cure. A major breakthrough in the last decade was the discovery of a loss-of-function single gene mutation identified in up to 80% of cases of hereditary form of PAH (HPAH), and about 25% of patients with sporadic idiopathic PAH (IPAH). The gene responsible is called BMPR2 (bone morphogenetic protein receptor 2), which is crucial to maintaining healthy pulmonary vessels. In particular, the integrity, function and survival of an important cell type known as the endothelial cell (EC) which forms the lining of vessels in the lung is critically dependent on fully functional BMPR2. In fact, the loss of lung ECs has been hypothesized to be the initiating event that triggers PAH. However, the molecular mechanisms of BMPR2 mutations are unclear and there are no specific treatments for this patient population thus far. Using an approach known as proteomics, we will study the direct effect of the BMPR2 mutation on the entire complement of proteins in ECs derived from peripheral blood of HPAH patients with BMPR2 mutations. Using this powerful technology, we can also detect molecular modifications that reflect changes protein activity and derive a comprehensive profile of cellular processes affected by the BMPR2 gene mutation. With this information, we will validate the function of these targets in patient-derived ECs and in animal models of PAH to better understand the disease. We hope that the knowledge gained from this research will allow us to design personalized interventions aimed at preventing PAH in families with known mutations before the onset of disease, potentially relieving a huge burden on the individual and the health care system.