Heart failure is an abnormality of myocardial cell function resulting in impaired ventricular performance. The functional defect is unknown, but may be related to alterations in calcium (ca++) handling. Evidence suggests that the altered functional properties of the sarcoplasmic reticulum (SR) are in part related to a defect in the SR Ca++ ATPase pump as shown by the decreased expression of mRNA encoding the SR Ca++ ATPase gene in failing hearts. Recently transgenic technology has emerged as a valuable tool to study tissue specific and inducible gene expression in vivo. The goal of this project is to produce transgenic mice which overexpress cardiac SR Ca++ ATPase and apply it to a murine model of cardiac failure induced by pulmonary artery banding (PAB) that I have developed, to determine if SR Ca++ ATPase overexpression in heart failure can rescue the cardiac dysfunction. The present study proposes the following specific aims: 1) To characterize the in vivo murine model of compensated and decompensated heart failure produced by PA banding with respect to; a) The heart failure phenotype; hemodynamics, organ weights, and in vivo contractile function by digital contrast ventriculography. b) Genetic markers (expression of SR Ca++ ATPase, ANF, MLC-2 mRNA. 2) To produce transgenic mice using a MLC-2/SR Ca++ ATPase construct to overexpress SR Ca++ ATPase selectively in the ventricle. 3) To determine if overexpression of SR Ca++ ATPase can diminish the functional abnormality in failing hearts, the PAB model will be applied to transgenic mice which harbor the MLC-2 SR Ca++ ATPase transgene and characterized as in specific aim 1. 4) To assess myocardial calcium homeostasis in compensated and decompensated heart failure; Calcium transients in isolated papillary muscle from ventricles of normal and failing hearts which overexpress SR Ca++ ATPase will be determined.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08HL003041-04
Application #
2459855
Study Section
Special Emphasis Panel (ZHL1-CCT-M (M1))
Project Start
1994-08-01
Project End
1999-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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