PROJECT 2: Inflammation of Reperfused Mouse Heart: Gene Deletion The theme of Project 2 continues to be the definition of the cellular and molecular mechanisms that regulate leukocyte trafficking in the heart after myocardial ischemia. Development and characterization of mice deficient in cell adhesion molecules by ourselves and others have clearly demonstrated that the molecular mechanisms that regulate leukocyte trafficking are both stimulus and tissue specific. Recent studies in the mouse model of ischemia/reperfusion using mice deficient in CAMs have shown that alternative pathways can be utilized for leukocyte extravasation. In this application we will continue to pursue a molecular genetic approach, but the focus has shifted away from studying the role of leukocytes in potentiating injury to myocytes after ischemia/reperfusion to understanding the unique molecular mechanisms that control leukocyte infiltration in the heart after ischemic injury and the role of cell adhesion molecules in healing of the heart after ischemic injury. The following specific aims are proposed: 1) define cardiac-specific molecular mechanisms that regulate leukocyte trafficking with and without reperfusion after ischemic injury using mice deficient in cell adhesion molecules along with blocking monoclonal antibodies. 2) characterize potential mechanisms for tissue specificity by examining phenotyping and functional differences between murine cardiac microvascular endothelial cells and murine endothelial cells from the inferior vena cava, and explore potential mechanisms for stimulus specificity by comprehensively profiling mRNA levels for cytokines, chemokines, and their receptors in the heart after ischemic injury with and without reperfusion in a recently developed chronic closed chest model of murine ischemia and reperfusion; 3) characterization and identification of the molecular mechanisms for a novel pathway for the primary adhesion of leukocytes to endothelial cells that is induced by IL-4 and is independent of E-, P-, and L-selectin; 4) definition of the role of cell adhesion molecules in regulating repair and remodeling of the heart after ischemic injury by using mice deficient in cell adhesion molecules in the mouse model of myocardial infarction with chronic survival.
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