Inflammation in Vascular Injury and Repair

描述(由申请人提供)：炎症在 动脉粥样硬化和再狭窄中的血管损伤和修复。粘合剂 血管细胞之间的相互作用协调了这种炎症反应。 在这项资助期间，我们一直专注于白细胞整合素 Mac-I(CDI lb/CD18)，鉴定该黏附受体为分子 实验性动脉损伤后新生内膜增厚的决定因素。这些 研究揭示了新的信息，关于白细胞是如何在 血管损伤的部位及整合素的调控和启动 “由外而内”的信号，暗示整合素操纵的新机会 在体内发挥作用。这次续签申请的中心假设是 白细胞Mac-I与血小板GP Iba的相互作用介导白细胞 血管损伤后重新招募，Mac-I功能受 尿激酶受体(UPAR)，Mac-I聚集性促进促炎作用 驱动实验性血管成形术后新生内膜增厚的信号。这个 该提案的总体目标是定义Mac-i中介的角色 血管损伤和修复中的炎症。我们的具体目标是：(一) 确定相互作用的物理和功能决定因素 MAC-I、GP Ibalpha和Mac-I-UPAR；(2)表征诱导的信令事件 通过聚集促进基因表达的Mac-I；以及(3)确定 干扰Mac-I-GP LBA和Mac-I-uPAR对白细胞募集的影响 颈动脉损伤后细胞增殖和新生内膜增厚。 因为整合素的功能和信号转导是 炎症，了解血管炎症的分子机制 将为制定调节血管的策略提供必要的见解 修复再狭窄和其他加速的动脉病变，包括移植 血管病变和静脉移植物增生。

DESCRIPTION (Provided by applicant): Inflammation plays an essential role in vascular injury and repair in atherosclerosis and restenosis. Adhesive interactions between vascular cells orchestrate this inflammatory response. During the period of this grant, we have focused on the leukocyte integrin Mac-I (CDI lb/CD 18), identifying this adhesive receptor as a molecular determinant of neointimal thickening after experimental arterial injury. These studies have revealed novel information as to how leukocytes are recruited at sites of vascular injury and how integrins are regulated and initiate "outside-in" signals, suggesting new opportunities for manipulation of integrin function in vivo. The central hypotheses of this renewal application are that the interaction of leukocyte Mac-I with platelet GP Iba mediates leukocyte recruitment after vascular injury, that Mac-I function is regulated by the urokinase receptor (uPAR), and that Mac-I clustering promotes pro-inflammatory signals that drive neointimal thickening after experimental angioplasty. The overall objective of this proposal is to define the role of Mac-I-mediated inflammation in vascular injury and repair. Our specific aims are: (1) To define the physical and functional determinants of the interactions between Mac-I,GP Ibalpha and Mac-I -uPAR; (2) To characterize signaling events induced by clustering Mac-I that promote gene expression; and (3) To determine the effects of disrupting Mac-I-GP lba and Mac-I-uPAR on leukocyte recruitment, cellular proliferation, and neointimal thickening after carotid artery injury. Because integrin function and signaling are important components of inflammation, understanding the molecular mechanisms of vascular inflammation will provide insights necessary to develop strategies for modulating vascular repair in restenosis and other accelerated arteriopathies, including transplant vasculopathy and vein graft hyperplasia.