Integrin Signaling In Vascular Cells

描述（由申请方提供）：血管平滑肌细胞（SMC）生长和迁移异常可导致高血压、动脉粥样硬化和再狭窄。SMC的功能是由复杂的调节机制控制的，这部分是由与细胞外基质的相互作用所决定的。整合素是细胞外基质的主要受体，激活粘附依赖性信号传导途径，并与生长因子和G蛋白偶联受体相互作用以影响细胞功能。本申请的目的是了解整合素α V β 3依赖性信号传导如何影响SMC生长和迁移。我们观察到用β 3-整联蛋白的抗体抑制剂处理的野生型小鼠，而不是β 3-整联蛋白缺陷（β 3-/-）小鼠，被保护免于内膜增生的发展，并且已经发现培养的野生型和β 3-/-SMC的性质的差异，这可以解释我们的体内观察。基于我们的初步数据，我们假设整合素α V β 3依赖的细胞内信号传导通过不同的途径在刺激和静止的SMC中正向和负向调节SMC的生长和迁移。拟议的研究将利用遗传学、药理学和RNA干扰技术，在SMC功能的良好表征的细胞和动物模型中靶向整合素α V β 3。首先，我们将确定在刺激SMC中的α V β 3依赖性通路。我们的初步数据表明，α V β 3作为一个分子开关，以调节Rho家族GT3和控制粘着斑组装。我们将描述负责GTTR监管的机制。第二，基于我们的初步数据，我们已经确定了在细胞静止期下调p38 MAPK的α V β 3的作用。我们将使用p38 MAPK通路作为模型来了解α V β 3依赖性通路如何促进SMC静止。第三，我们将描绘的贡献，α V β 3的生理反应，在培养的血管和完善的小鼠模型动脉损伤。这些结果将提供具体的见解SMC α V β 3在再狭窄和动脉粥样硬化的功能，并可能有广泛的意义，了解α V β 3整合素在血管生成，骨质疏松症和其他疾病的功能。

DESCRIPTION (provided by applicant): Abnormal vascular smooth muscle cell (SMC) growth and migration contributes to hypertension, atherosclerosis, and restenosis. SMC function is controlled by complex regulatory mechanisms, which are governed in part by interactions with the extracellular matrix. Integrins, the predominant receptors for the extracellular matrix, activate adhesion-dependent signaling pathways and cross-talk with growth factor and G-protein coupled receptors to influence cellular functions. The objective of this application is to understand how integrin alphaVbeta3-dependent signaling influences SMC growth and migration. We observed that wild-type mice treated with an antibody-inhibitor of beta3-integrins, but not beta3-integrin-deficient (beta3-/-) mice, were protected from the development of intimal hyperplasia and have found differences in the properties of cultured wild-type and beta3-/- SMCs that may account for our in vivo observations. Based on our preliminary data, we hypothesize that integrin alphaVbeta3- dependent intracellular signaling positively and negatively regulates SMC growth and migration thorough distinct pathways in stimulated and quiescent SMCs. The proposed studies will utilize genetic, pharmacologic, and RNA interference techniques to target integrin alphaVbeta3 in well-characterized cellular and animal models of SMC function. First, we will identify alphaVbeta3-dependent pathways in stimulated SMCs. Our preliminary data indicates that alphaVbeta3 serves as a molecular switch to regulate Rho Family GTPase and control focal adhesion assembly. We will delineate the mechanism(s) responsible for GTPase regulation. Second, based on our preliminary data, we have identified a role for alphaVbeta3 in downregulation of p38MAPK during cellular quiescence. We will use the p38 MAPK pathway as a model to understand how alphaVbeta3-dependent pathways contribute to SMC quiescence. Third, we will delineate the contribution of alphaVbeta3 to physiologic responses in cultured vessels and well-established mouse models of arterial injury. These results will provide specific insights into the function of SMC alphaVbeta3 in restenosis and atherosclerosis and may have broad implications for understanding alphaVbeta3 integrin function in angiogenesis, osteoporosis, and other disorders.