Central to the ability of vascular cells to adhere to the extracellular matrix and to each other is an abundant supply of cell surface adhesion molecules that, in addition to influencing the adhesive phenotype of the cell, are also capable of transmitting signals into, and responding to signals from, the cell interior. Such post-ligand events occur by virtue of the ability of these transmembrane proteins to interact with intracellular kinases and phosphatases, G-proteins, adapter proteins, and cytoskeletal components. PECAM-1, (also known as CD31) is a 130 kDa member of the Immunoglobulin superfamily that is expressed on the surface of circulating platelets, monocytes, neutrophils, and selected T-cell subsets. It is also a major constituent of the endothelial cell intercellular junction, where up to one million PECAM-1 molecules are concentrated. The overall goal of this competitive renewal application is to build on recent progress in the field of PECAM-1 biology, and to continue to explore the functions of PECAM-1 in the different vascular and blood cells in which it is expressed. Specifically, over the next five-year period, we propose to: (1) determine the solution structure of the PECAM-1 cytoplasmic domain, (2) characterize the mechanisms involved in PECAM-1- mediated cytoprotection, and use the information gained to explore ways to modulate cellular susceptibility to apoptosis, and (3) determine the molecular mechanisms by which PECAM-1 affects endothelial cell responses involved in maintaining vascular integrity. Together, these studies comprise a coordinated, focused research program designed to improve our understanding of the function of this novel vascular cell adhesion and signaling molecule in the blood and vascular cells in which it is expressed. We expect that information derived from this investigation will lead to improved understanding of the molecules and events that regulate inflammation, thrombosis, tumorigenesis, and the immune response.
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