The goal of this program project grant is to develop novel approaches to prevent, slow or reverse the pathological structural and functional cardiac remodeling that takes place after a myocardial infarction (Ml). Ischemic heart disease is a major health problem with few effective therapies. Ml usually leads to congestive heart failure with premature death or severe functional disability. While many cardiac defects have been identified in the diseased heart, very few have been translated into novel therapies. The objective of this PPG is to define novel mechanisms of cardiac dysfunction after Ml and to test, in large animal models, novel approaches to block these pathological processes so that cardiac function is improved. The program involves 3 projects and 4 supportive cores. All project leaders are established investigators and they have all collaborated extensively over the past decade. Project 1 (Houser) will explore the idea that blocking excess Ca entry into microdomains that house pathological signaling molecules will reduce cardiac dysfunction and death after Ml. Project 2 (Molkentin) will determine if reducing the activity of PKC-alpha will promote increased myocyte contractility and reduce cell death. Project 3 (Koch) will interrupt abnormally activated adrenergic signaling cascades that lead to cell death and reduce new myocyte formation. Discovery experiments to define and validate those processes we hope to modify to improve post Ml structure and function will be done in small animal models. Final tests of developed therapeutic approaches will be done in a large animal model with structural and functional characteristics that are similar to those in humans, setting the stage for rapid translation of novel therapies to patients with ischemic heart disease. The 3 projects are supported by 4 cores. A large animal model (pig) core will perform all Ml procedures and cardiac evaluations. This core will also perform all therapeutic interventions. A cell and tissue core will perform small animal experiments and will evaluate the properties of cells and tissues from all animal studies. A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108806-03
Application #
8650316
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Program Officer
Wong, Renee P
Project Start
2012-05-07
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Temple University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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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Sharp 3rd, Thomas E; Schena, Giana J; Hobby, Alexander R et al. (2017) Cortical Bone Stem Cell Therapy Preserves Cardiac Structure and Function After Myocardial Infarction. Circ Res 121:1263-1278
Bouley, Renee; Waldschmidt, Helen V; Cato, M Claire et al. (2017) Structural Determinants Influencing the Potency and Selectivity of Indazole-Paroxetine Hybrid G Protein-Coupled Receptor Kinase 2 Inhibitors. Mol Pharmacol 92:707-717
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
Rengo, Giuseppe; Pagano, Gennaro; Filardi, Pasquale Perrone et al. (2016) Prognostic Value of Lymphocyte G Protein-Coupled Receptor Kinase-2 Protein Levels in Patients With Heart Failure. Circ Res 118:1116-24
Harper, Shavonn C; Brack, Andrew; MacDonnell, Scott et al. (2016) Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects? Circ Res 118:1143-50; discussion 1150
Zhang, Xiaoying; Ai, Xiaojie; Nakayama, Hiroyuki et al. (2016) Persistent increases in Ca(2+) influx through Cav1.2 shortens action potential and causes Ca(2+) overload-induced afterdepolarizations and arrhythmias. Basic Res Cardiol 111:4
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
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

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