CKIS AND CONTROL OF VASCULAR SMOOTH MUSCLE CELL CYCLE

描述(改编自《调查者摘要》)：新生内膜形成 动脉对损伤的常见反应和结果，部分来自血管 血管平滑肌细胞的增殖、迁移和结缔组织 队形。VSMC增殖反应的机制 有丝分裂信号被很好地描述；然而，细胞基因的作用 导致VSMCS从增殖剂转变为静止状态的产品 细胞周期G1期的状态还不是很清楚。目标是 这笔拨款的目的是研究p21和p27对血管平滑肌细胞周期的控制。 细胞周期蛋白依赖性激酶抑制物(CKIs)。通过G1和入境中转 进入S阶段需要细胞周期蛋白依赖性激酶(CDK)的作用，并且 CDKs通过蛋白质磷酸化和结合而失活 调控亚单位，包括细胞周期蛋白和细胞周期调节因子。CKI直接 参与丝裂原依赖性CDK调控的有p21和p27。在……里面 初步研究表明，p21通过以下途径抑制VSMC生长 细胞周期停滞于G1/S期并检测到p21和p27 在活体受损动脉的新生内膜中的时间模式 与血管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。 以及对它们表达调控可能在 血管疾病的治疗。根据这些研究，他们有 假设这些蛋白质通过它们的基因改变VSMC的增殖 有能力通过G1调节进程并进入S阶段 细胞周期。为了探索这一假设，他们建议：1)检查 P21和p27抑制VSMC G1期生长的机制；2)确定 P21和p27在动脉粥样硬化发生发展中的作用 P21-/-小鼠与apoE-/-小鼠杂交及血管损伤 P21-/-小鼠、p27-/-小鼠和双基因敲除小鼠；以及3)检查p21如何 和p27在小鼠动脉粥样硬化病变中的表达比较 这些蛋白在人类动脉粥样硬化病变和猪动脉粥样硬化模型中的表达 气球受伤。拟议的研究应界定下列机制 P21和p27改变血管损伤后VSMC的增殖 动脉粥样硬化通过调节细胞周期的能力而发展 G1期进展。对这些机制的理解应该会给我们带来洞察力 血管疾病的病理生理学，并确定是否 增强动脉中p21和p27的表达可能限制过度的血管平滑肌细胞 在这些疾病中的扩散。

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.