VASCULAR ADHESIVE PROTEINS

平滑肌细胞表型转化、迁移和存活 是新生内膜形成和血管重塑所必需的。这些事件 被认为是动脉粥样硬化管腔狭窄的先决条件 和再狭窄疾病。我们假设细胞/细胞外基质 相互作用调节平滑肌细胞的表型、运动和存活 作为对受伤的反应。为了检验这一假设，这项提议侧重于 黏附蛋白、骨桥蛋白和α-β3整合素。在第一个 目的：我们将检验骨桥蛋白促进血管修复的假设。 对损伤做出反应，并增加动脉粥样硬化病变的形成。我们 将使用基因定义的小鼠突变体来研究 骨桥蛋白与血管修复和动脉粥样硬化性疾病。在第二个 部分，我们将检验骨桥蛋白是一种生存因子的假设。 用于血管平滑肌细胞。骨桥蛋白的作用机制 对Fas诱导的死亡的保护作用将在体外描绘出来。在 第三部分，我们将检验黏附蛋白基因的假说 这两种表型均可调节血管平滑肌细胞的表达 细胞的状态，以及周围细胞外的性质 矩阵。我们将定义控制表型依赖的启动子区域 骨桥蛋白在体外和体内的表达，并描述骨桥蛋白在体内的表达 骨桥蛋白而不是纤维连接蛋白或层粘连蛋白诱导的机制 骨桥蛋白基因在体外培养血管平滑肌细胞中的表达。 最后，我们将测试alphavbeta3是否需要 大鼠动脉损伤后的平滑肌细胞迁移。这些 实验将确定关键的黏附蛋白和细胞外基质/细胞相互作用 血管平滑肌对损伤的反应所必需的。这些分子 而过程可能是旨在控制的治疗的有用目标 动脉粥样硬化性和再狭窄疾病。

Smooth muscle cell phenotype transition, migration and survival are required for neointimal formation and vascular remodeling. These events are thought to be prerequisites for luminal narrowing in atherosclerotic and restenotic diseases. We hypothesize that cell/extracellular matrix interactions regulate smooth muscle cell phenotype, movement, and survival in response to injury. To test this hypothesis, this proposal focuses on the adhesive proteins, osteopontin and alphavbeta3 integrin. In the first aim, we will test the hypothesis that osteopontin promotes vascular repair in response to injury and increases atherosclerotic lesion formation. We will use genetically defined mouse mutants to investigate the function of osteopontin in vascular repair and atherosclerotic disease. In the second part, we will test the hypothesis that osteopontin is a survival factor for vascular smooth muscle cells. The mechanism by which osteopontin protects against fas-induced death will be delineated in vitro. In the third part, we will test the hypothesis that adhesive protein gene expression in smooth muscle cells in regulated both by the phenotypic state of the cells, and by the nature of the surrounding extracellular matrix. We will define promoter regions which control phenotype-dependent expression of osteopontin in vitro and in vivo, and delineate the mechanism whereby osteopontin, but not fibronectin or laminin induced osteopontin gene expression in vascular smooth muscle cells in vitro. Finally, we will test the hypothesis that the alphavbeta3 is required for smooth muscle cell migration following arterial injury in the rat. These experiments will identify key adhesive proteins and ECM/cell interactions required for vascular smooth muscle responses to injury. These molecules and processes may be useful targets for therapies aimed at controlling atherosclerotic and restenotic disease.