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。 在此期间，我们重点研究了白细胞整合素 Mac-I（CDI Ib/CD 18），将该粘附受体鉴定为分子粘附受体。 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，关于白细胞是如何被募集的， 血管损伤的部位以及整合素如何调节和启动 “由外向内”信号，提示整合素操纵的新机会 在体内发挥作用。这一更新申请的核心假设是， 白细胞Mac-I与血小板GP Iba相互作用介导白细胞 在血管损伤后的募集中，Mac-I功能受血管损伤后的 尿激酶受体（uPAR），并且Mac-I簇集促进促炎性 实验性血管成形术后驱动新生内膜增厚的信号。的 本提案的总体目标是确定Mac-I介导的 炎症在血管损伤和修复中作用。我们的具体目标是：（1） 定义物理和功能决定因素之间的相互作用 Mac-I、GP Ibalpha和Mac-I -uPAR;（2）为了表征在细胞内诱导的信号传导事件， 通过聚类促进基因表达的Mac-I;和（3）为了确定 破坏Mac-I-GP 1ba和Mac-I-uPAR对白细胞募集的影响， 细胞增殖和颈动脉损伤后新生内膜增厚。 因为整合素的功能和信号传导是 炎症，了解血管炎症的分子机制 将提供必要的见解，制定战略，调节血管 再狭窄和其他加速性动脉病的修复，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.