PROTEIN KINASE C & CELL CYCLE IN VASCULAR INJURY

蛋白激酶C

• 批准号: 2460114
• 负责人: CAROLYN J SMITH
• 金额: $ 10.36万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2460114
• 关键词: DNA replication; aorta; biological signal transduction; blood vessel disorder; calcium channel; calcium channel blockers; cell cycle; cell growth regulation; diacylglycerols; enzyme activity; gel electrophoresis; immunoprecipitation; injury; inositol phosphates; isozymes; laboratory rat; northern blottings; protein kinase C; regulatory gene; tissue /cell culture; vascular smooth muscle; western blottings

DESCRIPTION (Adapted from Investigator's Abstract): This application for a FIRST Award examines the role of activation of protein kinase C in immediate early gene expression following balloon catheter-induced injury of the rat thoracic aorta (BAL). Enhanced smooth muscle cell (SMC) proliferation and migration account for the intimal thickening which results from BAL of the rat thoracic aorta. The imposition of stretch upon SMC is inevitable in BAL, which produces a greater SMC proliferative response as compared to endothelial denudation alone. Protein kinase C (PKC) inhibitors and calcium channel blockers are known to modulate SMC proliferation in vitro, and the latter compounds reduce proliferation following BAL in vivo. The fundamental goal of this application is to delineate early calcium dependent signal transduction mechanisms responsible for stretch-induced activation of quiescent SMC in vivo, which in association with humoral factors, results in activation of the SMC cell cycle. The first two Aims center upon BAL stretch-induced regulation of PKC in an in situ perfused aortic preparation. Aim 1 covers the time course and calcium dependence for stretch-induced activation and membrane translocation of both the calcium sensitive and insensitive PKC isoforms. Aim 2 characterizes the time course and requirements for biphasic generation of the PKC cofactor diacylglycerol and inositol 3,4,5-trisphosphate. These findings will be extended using SMC in vitro in Aim 3. This Aim will examine translocation and down regulation of specific PKCs during the G1 phase of the cell cycle in vitro. The SMC in the vessel wall possesses a "contractile" phenotype whose growth is inhibited by heparinoid molecules associated with the extracellular matrix. Compared to proliferating "synthetic" SMC in vitro, the perfusion model is more relevant in that stretch-related signal transduction mechanisms in situ are more likely to mimic the earliest activation response of quiescent SMC in vivo. It is recognized the PKC and cell cycle studies in the in vitro system reflects growth control in cells that are persistently proliferative and in which the modeling of stretch may be limited. However, these studies serve as a basis of subsequent investigation of the role of PKC on the regulation of the cell cycle in differentiated vessel wall SMC.

描述（改编自研究者摘要）：本申请 第一个奖项的研究蛋白激酶C的激活在 球囊导管损伤后即刻早期基因表达 大鼠胸主动脉（BAL）。 增强的平滑肌细胞（SMC） 增殖和迁移导致内膜增厚， 结果来自大鼠胸主动脉的BAL。 强加的拉伸 在BAL中不可避免地会产生更大的SMC， 与单独的内皮剥脱相比，增殖反应。 蛋白激酶C（PKC）抑制剂和钙通道阻断剂是已知的 在体外调节SMC增殖，并且后一种化合物降低 在体内BAL后的增殖。 这个项目的基本目标是 应用是描绘早期钙依赖性信号转导 牵张激活静止期平滑肌细胞的机制 在体内，与体液因素有关，导致 SMC细胞周期的激活。 前两个目标以BAL为中心 牵张诱导的原位灌注主动脉中PKC的调节 准备. 目的1涵盖了时间进程和钙依赖性， 牵张诱导的活化和膜转位， 钙敏感和不敏感的PKC亚型。 目标2描述了 PKC辅因子双相生成的时间过程和要求 二酰基甘油和肌醇3，4，5-三磷酸。 这些发现将 在目标3中使用SMC在体外进行扩展。 本目标将审查 G1期特异性PKCs的转位和下调 细胞周期的变化。 血管壁中的SMC具有 生长被类肝素抑制的“收缩”表型 与细胞外基质相关的分子。 相比 增殖“合成”SMC在体外，灌注模型是更多 与牵张相关的原位信号转导机制有关 更有可能模仿静止的最早的激活反应， SMC in vivo. PKC和细胞周期的研究在肿瘤的发生、发展中起着重要的作用。 体外系统反映了细胞的生长控制， 增殖性的，并且其中伸展的建模可能受到限制。 然而，这些研究可作为后续调查的基础， 蛋白激酶C在细胞周期调控中的作用 血管壁SMC。