TGF-BETA 1 RECEPTORS IN RESTENOSIS AND AGING

到目前为止，心血管疾病是老年人发病和死亡的最大原因。 令人信服的证据表明，与年龄相关的血管修复细胞变化是导致 老年人动脉粥样硬化的发病率增加。人们认为血管修复是一种“失败的死亡” 细胞在吸烟、高血压和高脂血症损伤后，会在血管壁上积聚。 我们已经证明了来自人类动脉粥样硬化的细胞对凋亡因子的功能性抵抗。 损伤，以及来自老龄Fisher 344大鼠的细胞。在这项关于延长功绩的提案中 奖，我们展示了细胞生物学和微阵列图谱的结合很可能已经确定了潜在的 这一缺陷的原因。人类病变细胞、药物处理细胞和老年啮齿动物动脉的微阵列图谱 细胞产生了一系列候选基因，这些基因可以抵抗细胞凋亡。有系统地 通过QPCR、Western Blot和强迫过表达分析这些靶点，我们可以确定BclXI 仍然是Fas诱导的与年龄相关的细胞凋亡抵抗的有力候选因素 结扎术。同样，细胞周期蛋白D1和S-MURF2仍然是转化生长因子耐药的可靠候选者。 在第二届功勋奖中，我们继续朝着了解具体目标的方向前进 控制血管细胞抗凋亡的机制。提出了三个具体目标：1)进一步 通过抑制siRNA恢复功能来确认这些靶点，并通过强制过度表达来诱导 敏感细胞的表型；2)使用微阵列和蛋白质组定义整个抗性途径 方法寻找适合干预的成分；3)确定调节 老化啮齿动物血管壁损伤形成过程中的抗性途径。这个 研究已经确定了新的治疗药物，如黄烷醇和天然葡萄皮卡坦醇。 产品，能够调节病变对细胞凋亡的抵抗力。建议的研究结果 研究将准确地定义这一机制，并确定其他可以干预的步骤。这个 这些研究的目标是确定进展中的动脉粥样硬化病变的诊断标志物以及 可以通过药物或遗传干预来调节的靶点，以防止积累 血管壁中的细胞，从而防止心脏病发作和中风。 表演场地(

Cardiovascular disease is by far the largest cause of morbidity and mortality in the elderly population. Compelling evidence indicates that age-related changes in vascular repair cells are a root cause of the increased incidence of atherosclerosis in the elderly. It is thought that a 'failure to die'by vascular repair cells leads to their accumulation in the vessel wall after injury by smoking, hypertension, and hyperlipidemia. We have documented functional resistance to apoptotic factors in cells derived from human atherosclerotic lesions, and in cells derived from aged Fisher 344 rats. In this proposal for an extension of the MERIT Award, we show that a combination of cell biology and microarray profiling has likely identified the underlying cause of this defect. Microarray profiling of human lesion cells, drug-treated cells, and aged rodent arteries and cells produced a list of candidate genes which could confer resistance to apoptosis. In systematic analysis of these targets by QPCR, Western Blot, and forced overexpression, we could determine that Bcl-XI remains a strong candidate for a causative factor in age-related resistance to apoptosis induced by fas ligation. Likewise, cyclin D1 and Smurf2 remain solid candidates as mediators of the resistance to TGF-fi>. In the second term of the MERIT Award, we continue toward the goal of understanding the specific mechanisms that control apoptotic resistance in vascular cells. Three Specific Aims are proposed: 1) further confirm these targets by siRNA inhibition to restore function, and by forced overexpressionto induce the phenotype in sensitive cells; 2) define the entire pathway of resistance using microarrays and proteomic methods to find components that are amenable to intervention; 3) determine the effect of modulating the resistance pathway on the course of injury-induced lesion formation in the aging rodent vessel wall. The studies have already identified novel therapeutic agents, such as flavopiridol and picetannol, a natural grape product, that are capable of modulating resistance to apoptosis in the lesion. The results of the proposed studies will precisely define the mechanism, and identify other steps that are amenable to intervention. The goal of these studies is to identify both diagnositic markers of advancing atherosclerotic lesions as well as targets which can be modulated by Pharmaceuticalsor genetic interventions to prevent the accumulation of cells in the vessel wall, and thereby prevent heart attacks and stroke. PERFORMANCE SITE(