权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

AGE DEPENDENT CONTROL OF VASCULAR SMOOTH MYOCYTE GROWTH

血管平滑肌细胞生长的年龄依赖性控制

基本信息

批准号：
2501706
负责人：
VINCENTE ANDRES
金额：
$ 8.22万
依托单位：
STEWARD ST. ELIZABETH'S MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-30 至 1999-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2501706
关键词：
aging cell cycle proteins cell growth regulation gene targeting genetically modified animals laboratory mouse laboratory rat transfection vascular smooth muscle

项目摘要

Aging is a major risk for atherosclerosis. Abnormal proliferation of vascular smooth muscle cells (VSMCs) is an integral part of atherosclerotic plaque formation. Recent studies performed in my laboratory have shown the temporally and spatially coordinated induction of cdk2 and its regulatory subunits, cyclins E and A, after angioplasty in the rat carotid artery. Expression of these factors was also seen in proliferating VSMCs within human restenotic lesions, suggesting that induction of cdks and cyclins may contribute to pathological VSMC growth in injured human arteries. Induction of the cdk inhibitor p27, through suppression of cdk2 activity and transcriptional repression of cyclin A gene expression, might limit VSMC growth at late time points after angioplasty, and adenovirus- mediated overexpression of p27 after angioplasty reduced intimal lesion formation. We have also shown that elements within the -209 to +79 cyclin E and -79 to +100 cyclin A promoter regions confer cell cycle- dependent transcriptional control in VSMCs. Previous studies by others have demonstrated that the proliferative response of VSMCs to balloon angioplasty is enhanced in aged rats, suggesting that age-related increased VSMC growth kinetics might contribute-to the increasing prevalence and severity of atherosclerosis seen with aging. The broad objective of this Proposal is to elucidate age-dependent changes in the cell-cycle machinery in VSMCs that may contribute to enhanced atherosclerosis with aging. The investigations outlined in Specific Aim I will characterize the kinetics of expression and activity of cell-cycle regulatory factors after angioplasty in young and old rats. The studies outlined in Specific Aim 2 will elucidate age-related changes in the transcriptional regulation of cyclin E and A gene expression in VSMCs. Investigations outlined in Specific Aim 3 will assess the relevance of p27 to VSMC growth and intimal lesion formation in young and old animals. These studies will include gain-of function experiments using an adenovirus vector directing the overproduction of p27, and loss-of function studies using p27-deficient mice. These studies should yield valuable mechanistic insights into the cell-cycle regulatory networks underlying age-related increased VSMC proliferation and, ultimately, enhanced intimal lesion formation seen with aging.

衰老是动脉粥样硬化的主要风险。异常增殖血管平滑肌细胞（VSMC）是血管平滑肌细胞的一个组成部分，动脉粥样硬化斑块形成。最近的研究在我的实验室已经证明了时间和空间协调诱导cdk 2及其调节亚基，细胞周期蛋白E和A，大鼠颈动脉血管成形术。这些因素的表达是也见于人再狭窄病变内增殖的VSMC，提示cdks和cyclins的诱导可能有助于病理性VSMC生长在受伤的人动脉中。诱导 CDK抑制剂p27，通过抑制CDK 2活性，细胞周期蛋白A基因表达的转录抑制，可能会限制血管成形术后晚期VSMC生长，腺病毒- 血管成形术后p27介导的过度表达减少了内膜损伤阵我们还证明了-209到+79范围内的元素细胞周期蛋白E和-79到+100细胞周期蛋白A启动子区赋予细胞周期- VSMCs中的依赖性转录控制。其他人先前的研究表明，老年大鼠血管平滑肌细胞对球囊血管成形术的反应增强，提示年龄相关的VSMC生长动力学增加可能导致动脉粥样硬化的患病率和严重程度增加看到了衰老。本提案的总体目标是阐明 VSMC细胞周期机制的年龄依赖性变化，导致动脉粥样硬化随着年龄的增长而增强。调查具体目标I中概述的方法将表征表达的动力学血管成形术后细胞周期调节因子的活性年轻和年老的老鼠具体目标2中概述的研究将阐明与年龄相关的转录调控的变化，细胞周期蛋白E和A基因表达。概述的调查具体目标3将评估p27与VSMC生长的相关性，年轻和老年动物内膜损伤形成。这些研究将包括使用腺病毒载体功能获得实验指导p27的过度产生，以及使用 p27缺陷小鼠。这些研究应该产生有价值的机制深入了解与年龄相关的细胞周期调控网络 VSMC增殖增加，最终内膜损伤增强随着年龄的增长而形成。