Inflammation is a key component of cardiovascular diseases and related pathophysiological processes, including atherosclerosis, autoimmunity, allograft rejection, the diabetes-metabolic syndrome, hemostasis and thrombosis, and wound healing. The vascular endothelium plays an active and vital role in regulating inflammatory responses and in maintaining homeostasis of the innate and adaptive immune systems. Two basic functions of the endothelium, particularly important in the context of inflammation, are the regulation of leukocyte recruitment and vascular permeability, both of which involve coordinated interactions of cell-cell adhesion/junctional molecules and the actin cytoskeleton. Dysregulation of these endothelial functions promotes inflammatory disease processes. Since its inception 30 years ago, this Program Project has combined cell and molecular biological, biochemical, morphological, molecular genetic, and experimental pathological approaches in in vitro cell culture and in vivo animal models to gain new insights into the active role of vascular endothelium in inflammation. In this amended renewal application, Project 1 will study the contribution of endothelial CD47 and its ligands Signal Regulatory Proteins and thrombospondin, as well as leukocyte CD47 dependent regulation of VLA-4 and LFA-1 integrin adhesion, in the recruitment of inflammatory mononuclear leukocytes into sites of chronic inflammation. Project 2 will examine the mechanisms by which endothelium selectively regulates recruitment of the IL17- and IFN-y producing subsets of T lymphocytes into tissues. Project 3 will determine how endothelial barrier function and leukocyte integrin-mediated adhesion may be selectively regulated by the subcellular compartmentalization of signaling by the intracellular mediator cAMP and its effectors molecules. In support of the scientific goals of these projects. Core A (Cell Biology) will provide well characterized vascular cell cultures (human, mouse, wildtype and mutant);monoclonal hybridoma cells and leukocyte cell lines;Core B (Morphology) will assist in immunohistochemistry and histopathology of mouse tissues;Core C (Physiological and Molecular Imaging) will support intravital and confocal microscopy studies as well as in vitro leukocyte-endothelial adhesion studies under defined flow conditions. Core D will provide administrative, secretarial and laboratory management support for the Program. The results of these proposed studies should yield valuable new insights into how vascular endothelial cells actively participate in the regulation of the inflammatory process, which is central to so many pathophysiological conditions that affect the heart and blood vessels (e.g., heart attacks and strokes), as well as other organs and tissues of the body. These mechanistic insights may help identify novel therapeutic targets for the treatment of a broad spectrum of inflammatory diseases.
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