Grant: Project Grant

Pulmonary arterial hypertension (PAH) is a fatal disease that preferentially targets young women in their 30s and 40s. PAH involves the disordered and uncontrolled growth of blood vessels in the lung. This overgrowth leads to obstruction of these vessels, increased stress on the right side of the heart and eventual death due to heart failure. PAH is strongly linked to mutations in a gene called BMPR2, which encodes a protein on the surface of lung vascular cells. Interactions of this protein with a circulating factor, known as bone morphogenetic protein-9, or BMP9, has been shown to restrain the growth of lung vascular cells in healthy people. However, our previous research has shown that when the BMPR2 gene is mutated or lost, as it is in some PAH patients, BMP9 instead promotes the excessive growth of these same vascular cells. Based on this information, we hypothesize that BMP9 can serve as a "switch" that either promotes or prevents vascular growth, depending on the expression level of the BMPR2 gene. The current project will use genetically modified mice, which lack BMPR2 selectively in their blood vessels, to study the effect of BMP9 on mouse models of PAH. Additional studies will aim to understand the molecular changes within vascular cells that drive the altered BMP9 response in disease. This information will ultimately be used to develop and test candidate drugs that restore the normal growth-limiting response to BMP9, even in disease states where BMPR2 is lost. Despite the approval of several new treatments, the annual mortality rate for PAH remains high (~15%/year). The proposed work will help to clarify a completely original phenomenon that drives disease progression, with the goal of developing new treatments that are grounded in the genetics of the human disease.