description): Congestive heart failure results in substantial structural and functional changes at the level of cardiac myocytes. Preliminary results indicate that the t-tubular network is severely depleted or absent in failing canine and human myocytes. This observation has important functional consequences for excitation-contraction (E-C) coupling (which requires close opposition between surface membrane L-type Ca channels (DHPRs) in the t-tubule membrane and Ca release channels (RyRs) in the SR) and beta-adrenergic signal transduction. The general hypothesis of the proposed research is that sub-cellular remodeling of the t-tubule system and junctional domains results in contractile failure and abnormal beta-adrenergic regulation in failing ventricular myocytes. This general hypothesis will be tested in myocytes obtained from a tachycardia pacing-induced dog model and confirmed on human cells obtained from patients undergoing cardiac transplantation. The 5 specific aims of the proposed research are: 1) characterization of the t-tubule system density in failing and control hearts using 2-photon and confocal microscopy, 2) quantification of DHPRs in failing and control hearts using electrophysiological and biochemical techniques, 3) define the mechanism of uncoupling of the DHPR and RyR in failing myocytes, 4) determine the mechanism of uncoupling of beta-adrenergic receptors and DHPRs, and 5) perform confocal immunolocalization studies of DHPR subunits, RyR, beta-adrenergic receptors and G-proteins.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061537-04
Application #
6537489
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Reinlib, Leslie
Project Start
1999-07-01
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2004-05-31
Support Year
4
Fiscal Year
2002
Total Cost
$292,992
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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