Role of ADAMs in Endothelial Inflammatory Response

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DESCRIPTION (provided by applicant): Activation of endothelial cells during inflammatory processes, such as atherosclerosis, results in a dynamic regulation of membrane-anchored adhesion molecules, receptors and ligands that modulate the inflammatory response. Leukocyte recruitment during the inflammatory response requires highly regulated leukocyte-endothelial interactions that include tethering and rolling, leukocyte activation, leukocyte arrest, followed by transendothelial cell migration. Members of the ADAM (A Disintegrin And Metalloproteinase) family of transmembrane proteins contain extracellular metalloproteinase that have been shown to be the "sheddases" for a diverse group of membrane-anchored proteins. Molecules involved in all stages of leukocyte recruitment have been shown to be "shed" and are detected as soluble proteins following inflammatory stimuli. However, the enzymes responsible for their shedding have not been identified. This proposal will investigate the role of endothelial-expressed ADAMs in the dynamic regulation of endothelial adhesion molecules and junction proteins required for leukocyte emigration by asking the following questions: 1) What is the contribution of ADAMs to ectodomain shedding of leukocyte adhesion molecules on activated endothelial cells? 2) Does ADAM-mediated shedding of endothelial junction proteins modulate their cell-cell interactions and/or barrier function? 3) How does perturbation of ADAM-mediated sheddase activity for endothelial adhesion molecules and junction proteins affect leukocyte recruitment and transmigration, in vitro and in vivo?