PECAM-INDEPENDENT TRANSENDOTHELIAL MIGRATION

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DESCRIPTION (Verbatim from Investigator's Abstract): The inflammatory response is a double-edged sword. Mobilization of leukocytes to a focus of inflammation is critical for the rapid resolution of infections and restoration of tissue damage resulting from a variety of injuries. On the other hand, most human pathology results from inflammation that is misdirected or prolonged with the result that host tissues are damaged as a result. Therefore, much attention has been directed toward understanding the molecular basis of inflammation in the hope of being better able to regulate it. Previous studies have demonstrated a crucial role for platelet/endothelial cell adhesion molecule-2 (PECAM) in transendothelial migration (TEM), the step in which leukocytes (WBC) enter inflamed tissues by squeezing between the tightly apposed endothelial cells (EC) lining the blood vessels. However, even under the most favorable circumstances, blocking PECAM function only blocks 80-90% of leukocyte influx. The residual 10-20% of WBC that are not blocked may represent a clinically significant population under chronic conditions. Furthermore, there may be inflammatory stimuli, vascular beds, or WBC types for which PECAM does not play a major role in TEM. The aims of this proposal are to identify molecules responsible for PECAM-independent (PECAM alternative) mechanisms of TEM. We have developed an in vitro assay that can distinguish a block in adhesion of WBC tot he apical surface of EC from a block in TEM. Using this assay, we have identified two candidate molecules. In aim 1 we will further characterize and clone HEC2, a novel membrane proteins on EBC and EC junctions that are involved in TEM. In aim 2, we will further characterize a leukocyte beta2 integrin that plays a unique role in TEM that is independent of its role in adhesion and dependent on blockade of PECAM. In aim 3, we will test predictions made in vitro in two murine models of acute inflammation in which we can distinguish a block in adhesion from a block in transmigration. We have generated mice that are genetically deficient in PECAM and mice in which PECAM does not function. These mice will be critical to evaluate PECAM-independent TEM.