Our program project consists of four projects and three cores which focus on the border zone and three cores which focus on the border zone in acute ischemia. The projects employ in-situ porcine heart, isolated perfused rabbit papillary muscles, cultured rat myocytes, and lipid bilayers, to monitor, model, and mimic the ionic/electrophysiologic changes which occur at the ischemic border and which result in ventricular fibrillation and sudden cardiac death. Dr. Gettes' project correlates the ionic and electrophysiologic events at the border zone in the in-situ porcine heart, with specific reference to areas of very slow conduction and potentially short reentry circuits, and determines as precisely as possible in the isolated perfused rabbit papillary muscle, the cause of the changes in action potential characteristics, conduction, and refractoriness, which occur at ischemic borders. Dr. Cascio evaluates the role of diffusion of gases, substrates, metabolites and vasoactive factors across the ischemic border on the ionic/electrophysiologic changes. It employs confocal microscopy in the perfused rabbit papillar muscle and a unique planar model of cultured rat myocytes. It pays particular attention to changes in intracellular calcium and pH and to the possibility of propagating calcium waves. Dr. Rosenberg studies the sarcolemmal L-type calcium channel incorporated into lipid bilayers to characterize the molecular mechanisms responsible for modulating these channels along ischemic borders. It mimics the conditions in the ischemic border by controlling the extracellular and intracellular ionic metabolic, and enzymatic conditions on both sides of the membrane to gain information which will help explain the electrophysiologic changes studied in projects. Dr. Meissner's project utilize lipid bilayers and the perfused rabbit papillary muscle to study the relationship between the protein structure of the calcium release channel in the sarcoplasmic reticulum and its regulation. It tests the hypotheses that the channel is multi-ligand gated, that the calcium is the principal regulator of the channel, and that changes in the intracellular ionic milieu associated with acute ischemia cause changes in channel function. The program involves investigators from the Departments of Medicine, Biochemistry, Biophysics, Cell Biology, Anatomy, Pharmacology, Biomedical Engineering, and Biostatistics, and extensive collaboration with investigators at North Carolina State University. The National Institutes for Environmental Health Sciences, Duke University, and the Universities of Bern and Amsterdam. We believe that the sharply focused and integrated studies which comprise our program will provide important new information concerning the role of the ischemic border zone in sudden cardiac death.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL027430-19
Application #
6330010
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Spooner, Peter
Project Start
1982-07-01
Project End
2002-11-30
Budget Start
2001-02-20
Budget End
2001-11-30
Support Year
19
Fiscal Year
2001
Total Cost
$1,331,895
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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Cascio, Wayne E; Yang, Hua; Muller-Borer, Barbara J et al. (2005) Ischemia-induced arrhythmia: the role of connexins, gap junctions, and attendant changes in impulse propagation. J Electrocardiol 38:55-9
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Stange, Mirko; Xu, Le; Balshaw, David et al. (2003) Characterization of recombinant skeletal muscle (Ser-2843) and cardiac muscle (Ser-2809) ryanodine receptor phosphorylation mutants. J Biol Chem 278:51693-702
Bidasee, Keshore R; Xu, Le; Meissner, Gerhard et al. (2003) Diketopyridylryanodine has three concentration-dependent effects on the cardiac calcium-release channel/ryanodine receptor. J Biol Chem 278:14237-48
Lemasters, John J; Qian, Ting; He, Lihua et al. (2002) Role of mitochondrial inner membrane permeabilization in necrotic cell death, apoptosis, and autophagy. Antioxid Redox Signal 4:769-81

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