Grant: Master's Award: Canada Graduate Scholarships

Pulmonary arterial hypertension (PAH) is a devastating disease that is defined by the uncontrolled growth of the cells lining the blood vessels of the lungs. This growth causes restriction and blockage of blood vessels, resulting in stress on the heart and eventual heart failure. Many therapies exist, but they mostly address the symptoms of PAH, and not the underlying factors promoting its progression. Because of this, 15% of patients die every year. Mutations in a gene encoding a cell surface protein called the bone morphogenetic protein receptor type II (BMPR-II) greatly increase the risk of developing PAH. In healthy individuals, a protein in blood called BMP9 binds this receptor to promote vascular stability through the activation of intracellular proteins called Smads. When BMPR-II is lost in PAH patients, this activation of Smads by BMP9 fails to shut off, causing proliferation of the endothelial cells lining blood vessels. We believe that this change is due to the loss of Nedd4-binding protein-3 (N4BP3), a protein that normally serves as a break for BMP9 and Smads. The goals of this project are to develop tools to track Smad activation in live endothelial cells and use these tools to investigate the effect of BMPR-II and N4BP3 loss on the timing and duration of this activation. The ultimate goal of this work is to identify N4BP3 as a new target for drug development that is grounded in the genetic basis of the disease.