CKIS AND CONTROL OF VASCULAR SMOOTH MUSCLE CELL CYCLE

描述（改编自研究者摘要）：新生内膜形成是 这是动脉对损伤的常见反应，部分原因是血管 平滑肌细胞（vsmc）增殖、迁移和结缔组织 阵 血管平滑肌细胞增殖反应的机制 促有丝分裂信号已被充分描述;然而，细胞基因的作用 导致VSMC从增殖转变为静止的产物 在细胞周期的G1期期间的状态不是很清楚。 目标 本基金的目的是研究p21和p27对VSMC循环的控制 细胞周期蛋白依赖性激酶抑制剂（CKIs）。 通过G1过境和入境 进入S期需要细胞周期蛋白依赖性激酶（CDK）的作用， CDK通过蛋白质磷酸化和与 调节亚基，包括细胞周期蛋白和CKIs。 CKI直接 与有丝分裂原依赖性CDK调节有关的是p21和p27。 在 初步研究表明，p21抑制VSMC生长， 阻滞在细胞周期的G1/S期，并检测到p21和p27 在体内损伤动脉的新生内膜中， 与内膜细胞增殖呈负相关。 这些发现 提示这些CKI通常可以限制内膜增生的程度 以及它们表达调节可能在 血管疾病的治疗。 根据这些研究，他们 假设这些蛋白质通过它们的作用改变VSMC增殖， 调节通过G1期进展和进入S期的能力 细胞周期 为了探索这一假设，他们建议：1）检查 p21和p27对vsmc细胞G1期生长阻滞的作用机制; 2）确定p21和p27对vsmc细胞G1期生长阻滞的作用机制 p21和p27在动脉粥样硬化形成中的作用 p21-/-小鼠与apoE-/-小鼠杂交，在血管损伤后， p21-/-小鼠、p27-/-小鼠和双基因敲除小鼠;以及3）检查p21-/-小鼠 和p27在小鼠动脉粥样硬化病变中的表达相比， 这些蛋白质在人类动脉粥样硬化病变和猪模型中的表达 气囊损伤 拟议的研究应确定机制， p21和p27改变血管损伤后VSMC的增殖 通过调节细胞周期的能力发展动脉粥样硬化 在G1中的进展。 对这些机制的理解应该有助于了解 血管疾病的病理生理学，并确定 增强p21和p27在动脉中的表达可限制过度的VSMC 这些疾病的扩散。

DESCRIPTION (Adapted from Investigator's Abstract): Neointima formation is a common response of arteries to injury and results, in part, from vascular smooth muscle cell (vsmc) proliferation, migration and connective tissue formation. The mechanisms by which VSMC proliferate in response to mitogenic signals are well-described; however, the role of cellular gene products which cause vsmcs to shift from a proliferative to a quiescent state during G1 phase of the cell cycle are not well-understood. The goal of this grant is to study control of VSMC cycle by p21 and p27 cyclin-dependent kinase inhibitors (CKIs). Transit through G1 and entry into the S phase requires the action of cyclin-dependent kinases (CDKs), and CDKs are inactivated by protein phosphorylation and association with regulatory subunits, including the cyclins and the CKIs. CKIs directly implicated in mitogen dependent CDK regulation are p21 and p27. In preliminary studies, they have demonstrated that p21 inhibits VSMC growth by arrest at the G1/S phase of the cell cycle and that p21 and p27 are detected in the neointima of injured arteries in vivo in a time pattern that inversely correlates with intimal cell proliferation. These findings suggest that these CKIs may normally limit the degree of intimal hyperplasia in vivo and that modulation of their expression may play a useful role in treatments for vascular diseases. On the basis of these studies, they have hypothesized that these proteins alter VSMC proliferation through their ability to regulate progression through G1 and entry into S phase of the cell cycle. To explore this hypothesis, they propose to: 1) examine the mechanism of G1 growth arrest of vsmcs by p21 and p27 in vitro; 2) determine the function of p21 and p27 in the development of atherosclerosis in p21-/-mice crossbred with apoE-/-mice and following vascular injury in p21-/-mice, p27-/-mice, and double knock-out mice; and 3) examine how p21 and p27 expression in mouse atherosclerotic lesions compares to expression of these proteins in human atherosclerotic lesions and in porcine models of balloon injury. The proposed studies should define the mechanisms by which p21 and p27 alter VSMC proliferation following vascular injury and during development of atherosclerosis through their ability to regulate cell cycle progression in G1. An understanding of these mechanisms should lend insight into the pathophysiology of vascular diseases, and determine whether enhancement of p21 and p27 expression in arteries may limit excessive vsmc proliferation in these diseases.