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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Adhikari, Bishow B
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Kim, Jihee; Grotegut, Chad A; Wisler, James W et al. (2018) ?-arrestin 1 regulates ?2-adrenergic receptor-mediated skeletal muscle hypertrophy and contractility. Skelet Muscle 8:39
Zhou, Hua-Lin; Stomberski, Colin T; Stamler, Jonathan S (2018) Cross Talk Between S-Nitrosylation and Phosphorylation Involving Kinases and Nitrosylases. Circ Res 122:1485-1487
de Lucia, Claudio; Gambino, Giuseppina; Petraglia, Laura et al. (2018) Long-Term Caloric Restriction Improves Cardiac Function, Remodeling, Adrenergic Responsiveness, and Sympathetic Innervation in a Model of Postischemic Heart Failure. Circ Heart Fail 11:e004153
Grisanti, Laurel A; Schumacher, Sarah M; Tilley, Douglas G et al. (2018) Designer Approaches for G Protein-Coupled Receptor Modulation for Cardiovascular Disease. JACC Basic Transl Sci 3:550-562
de Lucia, Claudio; Eguchi, Akito; Koch, Walter J (2018) New Insights in Cardiac ?-Adrenergic Signaling During Heart Failure and Aging. Front Pharmacol 9:904
Wang, Jialu; Hanada, Kenji; Gareri, Clarice et al. (2018) Mechanoactivation of the angiotensin II type 1 receptor induces ?-arrestin-biased signaling through G?i coupling. J Cell Biochem 119:3586-3597
Hayashi, Hiroki; Hess, Douglas T; Zhang, Rongli et al. (2018) S-Nitrosylation of ?-Arrestins Biases Receptor Signaling and Confers Ligand Independence. Mol Cell 70:473-487.e6
Rizza, Salvatore; Cardaci, Simone; Montagna, Costanza et al. (2018) S-nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy. Proc Natl Acad Sci U S A 115:E3388-E3397
Cannavo, Alessandro; Koch, Walter J (2018) GRK2 as negative modulator of NO bioavailability: Implications for cardiovascular disease. Cell Signal 41:33-40
Wang, Jialu; Gareri, Clarice; Rockman, Howard A (2018) G-Protein-Coupled Receptors in Heart Disease. Circ Res 123:716-735

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