The goal of this proposal is to elucidate the subcellular signaling pathways through which myocardium acutely adapts to ischemic stress. Such adaptation (termed ischemic preconditioning; IP) occurs in response to short, non-lethal episodes of myocardial ischemia and is manifest by a marked reduction in infarct size resulting from a subsequent lethal episode of ischemia. Thus, characterization of the underlying mechanisms of this adaptation will enhance understanding of irreversible myocyte injury and may lead to new and innovative clinical strategies in the therapy of acute myocardial infarction. Recent studies have implicated activation of protein kinases as important in adaptation to ischemic stress. However, to date, further analysis of these subcellular signaling pathways has been limited due to the complexity of intact animal models. In order to simplify analysis of these signaling pathways, the investigator has developed a model of in vitro ischemia in adult canine isolated ventricular myocytes. This proposal will test the hypothesis that myocardial ischemia initiates a signaling cascade which, working through activation of a sequence of protein kinases, results in cardioprotection through stabilization of the myocyte cytoskeleton. The proposed signaling pathways leading from myocardial ischemia to stabilization of the cytoskeleton will be dissected into a series of sequential events. In addition, the specific cytoskeletal targets stabilized by protein kinase activation will be evaluated. Experimental design will include morphologic, biochemical, and pharmacologic assessment of isolated myocytes subjected to myocardial ischemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059563-02
Application #
6183874
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1999-07-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$257,085
Indirect Cost
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
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