INTEGRIN aMb2:STRUCTURE AND ATHEROTHROMBOTIC FUNCTIONS

α-M-β 2是整联蛋白β 2亚家族的成员，调节多种白细胞介导的应答， 包括跨内皮迁移、氧化反应、再灌注损伤和细胞缀合物的形成， 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 在α-M-β 2的能力进行活化和功能作为受体的一个非常广泛的频谱 的配体。包括在α-M-β 2的配体库中的是ICAM-1，其表达并参与细胞凋亡。 白细胞在发炎的内皮细胞和纤维蛋白原（Fg）之间的牢固粘附和迁移; 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 被假设来解释配体识别的多样性。不同配体使用的α-M-β 2 α-M-1-结构域中的不同组氨基酸残基与受体接合。此外，alpha-M和 受体的β 2亚单位对携带α-M-β 2的细胞的粘附和迁移功能有不同的贡献。在目标1中，将通过比较ICAM-1与Fg和其他识别界面来测试镶嵌模型。 α-M-β 2，并测试结合不同残基的配体可以诱导不同信号传导的推论 细胞内的事件。ICAM-1和Fg的识别需要受体的激活，这取决于 在信号从亚基的胞质尾传递到胞外结构域时。这 已从结构上检查了α-IIb-β 3的机制。在目标2中，将检验以下假设： α-M-2和α-IIb-β 3的胞质尾部之间的结构差异将导致不同的机制， 活化、细胞骨架互连和细胞内信号传导。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中重要的过程。在目标3中， α-M-β 2及其多种配体Fg、GPIbalpha和JAM-3在形成和靶向这些白细胞中的作用 将在体外和体内检查衍生物。独特的见解、数据集、功能分析和突变体 已经开发了受体，并将用于解决这些假设。拟议的研究将 提供了对控制α-M-β 2激活，配体识别和 其后果是调节白细胞参与血栓形成和心血管病变。

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.