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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
4K08HL114643-04
Application #
9058142
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Colombini-Hatch, Sandra
Project Start
2013-08-15
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Smith, Jeffrey S; Lefkowitz, Robert J; Rajagopal, Sudarshan (2018) Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov 17:243-260
Smith, Jeffrey S; Nicholson, Lowell T; Suwanpradid, Jutamas et al. (2018) Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation. Sci Signal 11:
Rajagopal, Sudarshan; Shenoy, Sudha K (2018) GPCR desensitization: Acute and prolonged phases. Cell Signal 41:9-16
Dahhan, Talal; Alenezi, Fawaz; Samad, Zainab et al. (2017) Echocardiography in the Risk Assessment of Acute Pulmonary Embolism. Semin Respir Crit Care Med 38:18-28
Onaran, H Ongun; Ambrosio, Caterina; U?ur, Özlem et al. (2017) Systematic errors in detecting biased agonism: Analysis of current methods and development of a new model-free approach. Sci Rep 7:44247
Smith, Jeffrey S; Alagesan, Priya; Desai, Nimit K et al. (2017) C-X-C Motif Chemokine Receptor 3 Splice Variants Differentially Activate Beta-Arrestins to Regulate Downstream Signaling Pathways. Mol Pharmacol 92:136-150
Dahhan, Talal; Siddiqui, Irfan; Tapson, Victor F et al. (2016) Clinical and echocardiographic predictors of mortality in acute pulmonary embolism. Cardiovasc Ultrasound 14:44
Smith, Jeffrey S; Rajagopal, Sudarshan (2016) The ?-Arrestins: Multifunctional Regulators of G Protein-coupled Receptors. J Biol Chem 291:8969-77
Parikh, Kishan S; Rajagopal, Sudarshan; Fortin, Terry et al. (2016) Safety and Tolerability of High-dose Inhaled Treprostinil in Pulmonary Hypertension. J Cardiovasc Pharmacol 67:322-5
Ma, Zhiyuan; Mao, Lan; Rajagopal, Sudarshan (2016) Hemodynamic Characterization of Rodent Models of Pulmonary Arterial Hypertension. J Vis Exp :

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