INTEGRIN aMb2:STRUCTURE AND ATHEROTHROMBOTIC FUNCTIONS

α-M-β2是整合素β2亚家族的一员，调节多种白细胞介导的反应， 包括跨内皮细胞迁移、氧化反应、再灌注损伤和细胞结合物的形成， 与动脉粥样硬化、血栓形成、再狭窄和中风有关的共振。这些反应取决于 根据α-M-β2的激活能力和作为极广泛光谱的受体的功能 配位体。在α-M-β2的配位体中包括ICAM-1，它表达并参与 白细胞在炎症的内皮细胞和纤维蛋白原(Fg)之间牢固的黏附和移位； 参与血栓形成、先天免疫和白细胞-血小板结合。马赛克模型具有 被假设用来解释配体识别的多样性。不同配体使用的Alpha-M-Beta2 不同组氨基酸残基在α-M-L结构域与受体接合。此外，阿尔法-M和 受体的β2亚基对α-M-β2细胞的黏附和迁移功能有不同的作用。在目标1中，将通过比较ICAM-1与FG等人的识别接口来检验马赛克模型 Alpha-M-Beta2，并测试不同残基的配体可以诱导不同的信号转导的推论 单元格内的事件。ICAM-1和FG的识别需要激活受体，这取决于 当信号从亚单位的胞质尾部传输到胞外区域时。这 对α-IIb-β3的作用机制进行了结构研究。在目标2中，将检验假设 α-M-2和α-IIb-beta3胞质尾部的结构差异将导致不同的机制 激活、细胞骨架互连和细胞内信号传递。白细胞与血小板的相互作用 微粒的释放是动脉粥样硬化和血栓形成的重要过程。在目标3中， α-M-β2及其多个配体Fg、GPIbalpha和JAM-3在形成和靶向这些白细胞中的作用 衍生品将在体外和体内进行检测。独特的洞察力、数据集、功能分析和突变 受体已经被开发出来，并将用于解决这些假说。拟议的研究将 提供对控制α-M-β2激活、配体识别和 它的后果是调节白细胞参与血栓形成和心血管病理。

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