The objective of this Program Project is to define the mechanisms of inflammation and repair in the heart after ischemia and reperfusion. The Projects focus on transcription factors and radical messenger molecules that mediate the response to ischemia and reperfusion in vascular endothelial cells and cardiomyoctes. The specific objectives are to determine the following: (1) the molecular mechanisms that activate production of superoxide and nitric oxide in the heart following ischemia, (2) the role of the adaptor protein p66shc in mediating post-ischemic oxidant generation and myocardial injury, (3) the role of the transcription factor Stat3 in mediating the inflammatory response to myocardial ischemia-reperfusion injury, (4) the role of endothelial cell exocytosis in mediating inflammation after ischemia-reperfusion, and (5) the role of the transcription factor HIF-1 and its target gene products in protecting and repairing the heart after ischemia. The Program Project has 5 Projects and 3 Cores (Pathology, Animal, and Administrative/Statistical). The Projects will perform studies with purified proteins, cultured cells, isolated perfused hearts, and in-vivo murine animal models. The techniques will include molecular biology, gene expression profiling with cDNA arrays, gene transfer by recombinant adenoviral vectors, transfection of decoy oligonucleotides or interfering RNAs, use of bone marrow derived stromal cells, and use of mice with targeted genetic mutations. The Cores will provide histology, immunohistology, fluorescent confocal microscopy, and murine models of (1) myocardial ischemia-reperfusion with measurement of infarct size and assessment of left ventricular function by echocardiography and pressure-volume loops and (2) post-ischemic inflammation of the cremaster muscle with assessment of leukocyte trafficking by computer-assisted videomicroscopy. We anticipate that this Program Project will yield fundamental information about the cellular mechanisms of post-ischemic inflammation and cardiac repair, and will provide novel therapeutic approaches to reducing post-ischemic myocardial injury.
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