Vascular endothelium, interacting with circulating blood components, plays a central role in the pathogenesis of acute and chronic inflammation, immunologic reactions, vascular injury and repair, and atherosclerosis. Since its inception 15 years ago, this Program Project has combined cell biological, biochemical, morphological, immunological and molecular biological approaches to gain new insights into the active role of endothelium in these important disease processes. In this competitive renewal application, novel integrative pathophysiologic strategies are proposed to extend these studies, in both in vitro and in vivo models. Project 0001 will study endothelial-dependent mechanisms in acute inflammation, focusing on the role of E-SELECTIN (ELAM-1) and lL-8 in neutrophil recruitment; Project 0005 will define the molecular mechanisms of monocyte-endothelial interactions under flow conditions, focusing on L- SELECTIN (LAM-1) and its inducible endothelial receptor; PROJECT 3 will examine the role of VCAM-1 in mononuclear leukocyte recruitment in chronic inflammatory processes, using various approaches including a murine transgenic """"""""knockout""""""""; Project 0007 will dissect the bi-directional, functional interactions of endothelial cells and lymphocytes, in immunologic processes. including antigen presentation, helper T-cell activation and specific T-cell recruitment; Project 0009 will characterize transcriptional mechanisms controlling adhesion molecule (ELAM-1, VCAM-1) gene expression in vascular endothelium, utilizing in vitro and in vivo models. 9002 (Cell Biology Support) will provide well characterized human and murine vascular cell cultures, as well as videomicroscopy and computer-image analysis; 9005 (Transgenic Mouse/Embryonic Stem Cell Support) will support the development of murine genetic modification strategies; 9001 (Morphology Support) will assist in immunohistochemistry and histopathology of human and mouse tissues; 9003 (Molecular Biology Support) will synthesize oligonucleotides and peptides, and provide molecular biological support.
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