INTEGRIN aMb2:STRUCTURE AND ATHEROTHROMBOTIC FUNCTIONS

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

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Linked publications & trials

Abstract

Alpha-M-beta2, a member of the beta2 subfamily of integrins, regulates a wide variety of leukocyte-mediated responses,[unreadable] including transendothelial migration, oxidative responses, reperfusion injury and formation of cell-conjugates,[unreadable] resonses that are relevent to atherosclerosis, thrombosis, restenosis and stroke. These responses depend[unreadable] upon the capacity of alpha-M-beta2 to undergo activation and function as a receptor for an extremely broad spectrum[unreadable] of ligands. Included within the ligand repertoire of alpha-M-beta2 is ICAM-1, which is expressed and participates in the[unreadable] firm adhesion and transmigration of leukocytes across inflamed endothelial, and fibrinogen (Fg); which[unreadable] participates in thrombus formation, innate immunity and leukocyte-platelet conjugation. A mosaic model has[unreadable] been hypothesized to explain the diversity of ligand recognition by. Alpha-M-beta2 in which different ligands use[unreadable] different sets of amino acid residues in the alpha-M-l-domain to engage the receptor. Moreover, the alpha-M and[unreadable] beta2 subunits of the receptor contribute differently to adhesive and migratory functions of alpha-M-beta2-bearing cells. In Aim 1, the mosaic model will be tested by comparing the recognition interface of ICAM-1 with Fg and other[unreadable] alpha-M-beta2 and to test the corollary that igands which engage different residues can induce different signaling[unreadable] events within the cells. The recognition of ICAM-1 and Fg requires activation of the receptor, which depends[unreadable] upon transmission of a signal from the cytoplasmic tails of the subunits to the extracellular domain. This[unreadable] mechanism has been examined structurally for alpha-IIb-beta3. In Aim 2, the hypothesis will be tested that the[unreadable] structural differences between the cytoplasmic tails of alpha-M-2 and alpha-IIb-beta3 will lead to distinct mechanisms of[unreadable] activation, cytoskeletal interconnections and intracellular signaling. Leukocyte interaction with platelets and[unreadable] release of microparticles are processes that are important in atherosclerosis and thrombosis. In Aim 3, the[unreadable] role of alpha-M-beta2 and its multiple ligands, Fg, GPIbalpha and JAM-3, in forming and targeting these leukocyte[unreadable] derivatives will be examined in vitro and in vivo. Unique insights, data sets, functional assays and mutant[unreadable] receptors have been developed and will be used to address these hypotheses. The proposed studies will[unreadable] provide an understanding of the molecular mechanisms that govern alpha-M-beta2 activation, ligand recognition and[unreadable] its consequences that regulate the participation of leukocytes in thrombosis and cardiovascular pathologies.