This proposal encompasses 6 collaborative investigations, supported by 3 integrated core facilities, to address issues fundamental to the etiology, pathogenesis and treatment of cardiac failure. The studies are focused in an attempt to unravel the molecular basis underlying cardiac growth and hypertrophy, post ischemic dysfunction following reperfusion and coronary occlusive disease post-transplantation. We will attempt to isolate the genes responsible for two inherited cardiac disorders: hypertrophic cardiomyopathy, whose underlying biochemical defects may also help to clarify mechanisms for acquired cardiac hypertrophy, and myotonic dystrophy, which in contrast, affects particularly the cardiac conduction system. We will clone the human cardiac sodium channel and analyze its structure-function relationships by site-directed mutagenesis and expression in Xenopus oocytes, as a first step toward rational design of anti-arrhythmic drugs which focus on transcriptional control of alpha-actin genes during cardiac myogenesis and hypertrophy, including the isolation of promoter-binding transcription factors that control actin gene expression. In situ hybridization will be used, to identify the expression of each alpha-actin gene in cardiac development, experimental hypertrophy, and clinical failure. We will elucidate the molecular mechanisms responsible for acute cardiac failure following ischemia and reperfusion, using EPR spectroscopy and spin trap agents to quantify the in vivo generation of oxygen-free radicals in the conscious dog, NMR spectroscopy to detect potential toxic metabolites in isolated hearts, and implantable Doppler probes to assess effects of anti-oxidants on ventricular dysfunction in patients after cardiac surgery. Using pigs specially bred for major histocompatibility complex, we will determine the immune and non-immune factors contributing to accelerated atherosclerosis after transplantation. These studies should provide significantly new insights into the molecular basis of cardiac failure and a rational basis for more effective therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL042267-05
Application #
2220374
Study Section
Special Emphasis Panel (SRC (SL))
Project Start
1990-01-01
Project End
1994-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Hartley, Craig J; Reddy, Anilkumar K; Madala, Sridhar et al. (2011) Doppler velocity measurements from large and small arteries of mice. Am J Physiol Heart Circ Physiol 301:H269-78
Garcia-Gras, Eduardo; Lombardi, Raffaella; Giocondo, Michael J et al. (2006) Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 116:2012-21
Senthil, Vinitha; Chen, Suet N; Tsybouleva, Natalie et al. (2005) Prevention of cardiac hypertrophy by atorvastatin in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circ Res 97:285-92
Marian, A J (2005) On mice, rabbits, and human heart failure. Circulation 111:2276-9
Tsybouleva, Natalia; Zhang, Lianfeng; Chen, Suetnee et al. (2004) Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation 109:1284-91
Marian, Ali J (2003) On predictors of sudden cardiac death in hypertrophic cardiomyopathy. J Am Coll Cardiol 41:994-6
Nagueh, Sherif F; McFalls, Judy; Meyer, Denise et al. (2003) Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Circulation 108:395-8
Marian, A J; Roberts, R (2003) To screen or not is not the question--it is when and how to screen. Circulation 107:2171-4
Marian, A J (2002) Modifier genes for hypertrophic cardiomyopathy. Curr Opin Cardiol 17:242-52
Hartley, Craig J; Taffet, George E; Reddy, Anilkumar K et al. (2002) Noninvasive cardiovascular phenotyping in mice. ILAR J 43:147-58

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