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 #
1P01HL108806-01A1
Application #
8266930
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Wong, Renee P
Project Start
2012-05-07
Project End
2017-03-31
Budget Start
2012-05-07
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$2,305,267
Indirect Cost
$669,417
Name
Temple University
Department
Physiology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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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
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