The overall theme of the above PPG application will continue to be the identification of novel signaling molecules and pathways that contribute to the pathogenesis of heart failure (HF) after cardiac injury and also to study potential intersecting signaling and cellular mechanisms for repair of compromised myocardium. The proposal specifically will aim to identify critical molecular targets involved in abnormal myocardial responses to stress and subsequent repair or reversal of cardiac injury. Importantly, our studies will be done with a vision towards identifying new therapeutic strategies for reversing HF, which is something desperately needed as the incidence of this devastating disease continues to rise. Although improvements have been made in the management of HF, deaths are still increasing and it is imperative to find more effective therapies. Our efforts will come from multiple but complimentary directions and all investigators will use newly developed mouse models to test individual project hypotheses focused on the PPG theme. This PPG is being led by project leaders who are distinguished scientists in the HF arena with a long history of productivity, and who are all faculty at Temple University School of Medicine. The fact that all members are in the same building should only enhance our close collaborations that have led to success over the first funding cycle of and which has produced the described integrative projects in the current application. The themes of each project are: Project 1 (Koch) will study how the novel activity of G protein-coupled receptor kinase-5 (GRK5), including in the nucleus, alters myocardial responses to hypertrophic and ischemic stress that injure the heart to promote remodeling and eventual HF;Project 2 (Feldman) will investigate novel roles of arginine vasopressin (AVP) type 1A receptors in cardiac injury induction and protection, including differential mechanistic involvement of G protein- versus GRK-biased signaling in these processes;Project 3 (Houser) will study how calcium (Ca2+) entry through specific transient receptor potential (TRP) channels alter hypertrophic and remodeling processes of the heart following cardiac injury and how their modification by G protein signaling molecules and protein kinases may influence downstream signaling events. These three projects will continue to be supported by four Core units: Administrative (Koch);Mouse Physiology/Surgery (Gao);Molecular and Cellular Imaging (Tilley);and Gene Vector (Rabinowitz). Importantly, all Project leaders have expertise in translating their basic science results/discoveries, which represents a strength of our program.

Public Health Relevance

Heart Failure remains a major health problem and there continues to be a need to develop innovative treatments to minimize cardiac injury and repair the failing heart. Understanding molecular mechanisms involved in cardiac injury and repair is imperative in order to begin to develop these novel therapies. All projects within this Program Project have goals to move towards translating discoveries and developing novel therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL091799-06A1
Application #
8667002
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Schwartz, Lisa
Project Start
2008-05-01
Project End
2019-04-30
Budget Start
2014-05-05
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
$2,312,979
Indirect Cost
$827,921
Name
Temple University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Wasilewski, Melissa A; Myers, Valerie D; Recchia, Fabio A et al. (2016) Arginine vasopressin receptor signaling and functional outcomes in heart failure. Cell Signal 28:224-33
Feldman, Arthur M; Gordon, Jennifer; Wang, JuFang et al. (2016) BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes. J Mol Cell Cardiol 92:10-20
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Woodall, Benjamin P; Woodall, Meryl C; Luongo, Timothy S et al. (2016) Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy. J Biol Chem 291:21913-21924
Traynham, Christopher J; Hullmann, Jonathan; Koch, Walter J (2016) ""Canonical and non-canonical actions of GRK5 in the heart"". J Mol Cell Cardiol 92:196-202
Khan, Mohsin; Koch, Walter J (2016) c-kit+ Cardiac Stem Cells: Spontaneous Creation or a Perplexing Reality. Circ Res 118:783-5

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