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)
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
Project End
Budget Start
Budget End
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
Molkentin, Jeffery D (2014) Letter by Molkentin regarding article, "The absence of evidence is not evidence of absence: the pitfalls of Cre Knock-Ins in the c-Kit Locus". Circ Res 115:e21-3
Hullmann, Jonathan E; Grisanti, Laurel A; Makarewich, Catherine A et al. (2014) GRK5-mediated exacerbation of pathological cardiac hypertrophy involves facilitation of nuclear NFAT activity. Circ Res 115:976-85
van Berlo, Jop H; Kanisicak, Onur; Maillet, Marjorie et al. (2014) c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509:337-41
Scimia, Maria C; Gumpert, Anna M; Koch, Walter J (2014) Cardiovascular gene therapy for myocardial infarction. Expert Opin Biol Ther 14:183-95
Davis, Jennifer; Molkentin, Jeffery D (2014) Myofibroblasts: trust your heart and let fate decide. J Mol Cell Cardiol 70:9-18
Correll, Robert N; Eder, Petra; Burr, Adam R et al. (2014) Overexpression of the Na+/K+ ATPase ?2 but not ?1 isoform attenuates pathological cardiac hypertrophy and remodeling. Circ Res 114:249-56
Duran, Jason M; Makarewich, Catherine A; Trappanese, Danielle et al. (2014) Sorafenib cardiotoxicity increases mortality after myocardial infarction. Circ Res 114:1700-12
Barr, Larry A; Makarewich, Catherine A; Berretta, Remus M et al. (2014) Imatinib activates pathological hypertrophy by altering myocyte calcium regulation. Clin Transl Sci 7:360-7
Makarewich, Catherine A; Zhang, Hongyu; Davis, Jennifer et al. (2014) Transient receptor potential channels contribute to pathological structural and functional remodeling after myocardial infarction. Circ Res 115:567-80
Houser, Steven R (2014) Role of RyR2 phosphorylation in heart failure and arrhythmias: protein kinase A-mediated hyperphosphorylation of the ryanodine receptor at serine 2808 does not alter cardiac contractility or cause heart failure and arrhythmias. Circ Res 114:1320-7; discussion 1327

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