The overall objective of the Grant in the past was to characterize the inflammatory response and inflammatory injury after reperfusion of the infarcted myocardium. In recent years, we have shifted our emphasis to include the role of inflammation in cardiac repair and cytoprotection. We hypothesize that the cellular and molecular components of cardiac inflammation evolved as a protective mechanism for the organism with a potential role in tissue repair and cytoprotection. We hypothesize that the cellular and molecular components of cardiac inflammation evolved as a protective mechanism for the organism with a potential role in tissue repair and cytoprotection. Project 1 examines three reperfusion dependent events, which may modulate tissue: 1) Phenotypic transition of neutrophils as a major source of fibrogenic and angiogenic factors, 2) Mast cell recruitment in tissue repair and scar formation, and 3) Reperfusion dependence of early chemokine induction in cardiac venular endothelial and its downstream significance. Project 2 utilizes genetic deletions of specific cell adhesion molecular to define: 1) cardiac specific molecular mechanisms regulating leukocyte trafficking, 2) differences between cardiac microvascular endothelium and venous endothelium, 3) novel pathways for primary adhesion of leukocytes which are independent of known selectins, and 4) the role of cell adhesion molecules in tissue repair of the heart. Project 3 examines both positive and negative controllers of leukocyte adhesion and trafficking focusing on 1) shear dependent activation of leukocyte functions effected by selectin binding, the role of LFA-1 under shear and novel factors in adhesion and signaling. Project 4 is a new project which arises from work in the current grant period that demonstrated reperfusion-dependent induction of myocyte cytokines (TNF-alpha), IL-6, and LIF). Studies in the current grant period, suggest that inflammatory cytokines could potentially by cytoprotective. The project will study the mechanism of these cytoprotective effects specifically focusing on their anti-apoptotic effects of the molecular basis for them. The projects share methods and experimental paradigms. In addition to an Administrative Core, the application continues the Animal Core and Cell Biology Core that have produce many of our unique models.
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