Noncanonical Receptor Signaling in Pulmonary Arterial Hypertension

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DESCRIPTION (provided by applicant): 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.