The goal of our revised PPG is to identify novel molecules and pathways that have the potential to become therapeutic targets in the treatment of heart failure with a theme centered on signaling mechanisms of adrenergic receptors. In this revised application, we will continue the fantastic collaborative environment that has characterized this PPG. Based on natural collaborations that were already in place between Rockman, Koch, Stamler and Lefkowitz, and which have flowered during the PPG, we have developed an integrated approach to identifying novel betaAR signaling mechanisms. Over the past funding cycle, this has led to a number of high impact publications and the identification of novel mechanisms of betaAR signaling. The experimental organization is crafted so that the specific aims for each project address both basic molecular mechanisms of GPCR signaling using in vitro and cell culture methods, and the translation of these fundamental concepts into relevant in vivo models of hypertrophy and heart failure. We propose 3 projects that each addresses a unique aspect of adrenergic signaling and which will be directed by project leaders that are distinguished scientists in their field. The themes for each project are: Project 1 (Rockman) will study novel aspects of betaAR signaling that uses beta-arrestin to promote cardiomyocyte cell survival pathways in the absence of G protein activation;Project 2 (Koch) will study novel aspects of the G protein-coupled receptor kinase-2(GRK2), and its important roles in the signaling and physiology of the heart;Project 3 (Stamler) will study a newparadigm for PAR signaling through regulation by S-nitrosylation of GRK and ?-arrestin. We also propose two scientific cores that are integral to the success of the program by providing both small animal expertise, where our discoveries at the bench can be tested in vivo, and proteomic and viral resources that will synergistically enhance the projects potential to discover new signaling proteins and pathways. The overall goal of this revised PPG is to explore the interplay of two universal mechanisms for signaling by betaARs, activation of G proteins and beta-arrestins, and how these are regulated by post-translational modifications (phosphorylation, ubiquitination, S-nitrosylation) of various signaling components. The results will be used to define novel strategies for manipulation of these recently discovered mechanisms for the therapy of patients with heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL075443-08
Application #
8323340
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Adhikari, Bishow B
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$1,826,364
Indirect Cost
$462,974
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Schumacher, Sarah M; Koch, Walter J (2017) Noncanonical Roles of G Protein-coupled Receptor Kinases in Cardiovascular Signaling. J Cardiovasc Pharmacol 70:129-141
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Jean-Charles, Pierre-Yves; Yu, Samuel Mon-Wei; Abraham, Dennis et al. (2017) Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of ?-adrenergic receptor signaling. JCI Insight 2:
Elphinstone, Robyn E; Besla, Rickvinder; Shikatani, Eric A et al. (2017) S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria. Infect Immun 85:
Waldschmidt, Helen V; Homan, Kristoff T; Cruz-Rodríguez, Osvaldo et al. (2016) Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors. J Med Chem 59:3793-807
Zhang, Rongli; Hess, Douglas T; Reynolds, James D et al. (2016) Hemoglobin S-nitrosylation plays an essential role in cardioprotection. J Clin Invest 126:4654-4658

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