This proposal is for a five-year research program for a future junior faculty member, Dr. Sudarshan Rajagopal, in studying cardiovascular signaling under the mentorship of Dr. Robert Lefkowitz. Dr. Rajagopal is currently in his fellowship training in cardiovascular medicine at Duke University Medical Center and plans to further his scientific training with mentored research in Dr. Lefkowitz's laboratory. Dr. Lefkowitz has been a leader in the field of cardiovascular signaling for over three decades and has a long track record of training successful physician-scientists. The research program will include specialized instruction, attendance at scientific meetings, and an advisory committee that will broaden the training experience and foster career development as a physician-scientist. In preliminary studies, we have identified a novel role for the multifunctional adapter ?- arrestin (?arrs) proteins. In addition to their canonical role in signaling by G protein-coupled receptors (GPCRs), we have found that ?arrs also regulate signaling by the type II bone morphogenetic protein receptor (BMPR-II), a TGF-? receptor. In humans, loss-of-function mutations of BMPR-II are associated with the development of pulmonary arterial hypertension (PAH), and we have found that ?arr knockout mice have markedly altered development of PAH in response to chronic hypoxia.
The aims of this proposed research are to: 1) Determine the role of ?arrs in signaling by endothelin and prostacyclin receptors, drug targets in the treatment of PAH;and 2) Characterize cross-talk between the GPCR and TGF-? receptor signaling axes in PAH. We expect these studies to yield important mechanistic insights into how ?arrs regulate signaling by these two classes of receptors and how such regulation could be exploited for therapeutic benefit in PAH.
Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature that results in increased stress on the right side of the heart. This ultimately leads to right ventricular failure and cardiovascular collapse. PAH is a rare disease with an incidence of 15 per million in the United States and its study is supported by the NIH Office of Rare Diseases Research. There is no cure for PAH and in registries prior to current therapies, the mean survival of patients was only 2.8 years. Even with current therapies, which cost tens of thousands of dollars per year, the prognosis of PAH continues to be poor, with a mean survival of 70% at 3 years. This study will lead to a better understanding of signaling by receptors that are targets in the treatment of PAH and could lead to the development of novel therapies for this morbid disease.