TGF-BETA 1 RECEPTORS IN RESTENOSIS AND AGING

描述：高龄是高血压的单一最强危险因素。 动脉粥样硬化的发展是动脉粥样硬化的主要原因 心肌梗死和卒中的易感因素。几行 有证据表明，动脉粥样硬化的损伤是慢性愈合的伤口， 由于未知的原因，未能倒退。我们发现了一个与年龄有关的 大鼠和人血管增殖和凋亡反应的缺陷 平滑肌细胞(SMC)会削弱其经历退化的能力 当出现适当的信号时。这种对细胞凋亡的抵抗 回归与2型受体(TbetaR-2)的特异性丢失有关 转化生长因子-β1(TGF-β1)。TbetaR-2的低表达 使来自老年动物和人类动脉粥样硬化病变的SMC对 转化生长因子-β1诱导的细胞生长抑制和细胞凋亡。在一些患者中，丧失 II型受体是由于TbetaR-2的移码突变所致。然而，大多数 由于TbetaR-2转录减少，病变细胞具有抵抗力。vbl.使用 基因组阵列，它被确定为人类病变，以及病变细胞系， 过量表达Egr-1，一种关于控制密钥的锌指转录因子 压力反应基因。在新的研究中，我们证明了Egr-1是一种强大的 TbetaR-2启动子的转录抑制因子，并对 转化生长因子-β。拟议的研究将确定Egr-1 抑制TbetaR-2，确定Egr-1升高的原因，并确定 升高的Egr-1在病变细胞中的下游后果。通过定义 Egr-1诱导抗性的原因和机制，我们计划开发手段 去改正它。转基因SMC移植将用于 评估升高的Egr-1和转化生长因子-β抵抗在发育中的作用 与年龄相关的内膜增生症。结果将确定原因和 导致非肿瘤性转化生长因子β1受体缺陷的后果 人冠状动脉和颈动脉的异常纤维化和增殖行为 动脉SMC。这种与年龄相关的转化生长因子-β1受体功能障碍是 在这些细胞中对抑制的广泛抵抗力，因此，潜在地直接 参与动脉粥样硬化、再狭窄及相关疾病的发展 在老年人群中流行的纤维增生性疾病。

DESCRIPTION: Advancing age is the single strongest risk factor for the development of atherosclerosis Underlying atherosclerosis is the major predisposing factor to both myocardial infarction and stroke. Several lines of evidence suggest that atherosclerotic lesions are chronically healing wounds, that for unknown reasons, fail to regress. We have identified an age-related defect in the proliferative and apoptotic responses of rat and human vascular smooth muscle cells (SMC) that would impair their ability to undergo regression when presented with appropriate signals. This resistance to apoptotic regression is related to the specific loss of Type II receptors (TbetaR-2) for transforming growth factor-beta1 (TGF-beta1). Reduced expression of TbetaR-2 makes SMC from old animals and from human atherosclerotic lesions resistant to growth inhibition and apoptosis induced by TGF-beta1. In some patients, loss of the Type II receptor is due to frame-shift mutations in TbetaR-2. However, most lesion cells are resistant due to reduced transcription of TbetaR-2. Using genomic arrays, it was determined that human lesions, and lesion cell lines, over express Egr-1, a about zinc-finger transcription factor that controls key stress-responsive genes. In new studies, we demonstrate that Egr-1 is a strong transcriptional suppressor of the TbetaR-2 promoter, and confers resistance to TGF-beta. The proposed studies will define the mechanism by which Egr-1 suppresses TbetaR-2, determine the cause of the elevated Egr-1, and determine downstream consequences of elevated Egr-1 in lesion cells. By defining the cause and mechanisms of Egr-1-induced resistance, we plan to develop the means to correct it. Transplantation of genetically modified SMC will be used to evaluate the role of elevated Egr-1 and TGF-beta resistance in the development of age-related intimal hyperplasia. The results will identify the causes and consequences of a non-neoplastic TGF beta1 receptor defect that leads to dysregulated fibrotic and proliferative behavior in human coronary and carotid artery SMC. This age-related TGF-beta1 receptor dysfunction is a component of a broad resistance to inhibition in these cells and thus, is potentially directly involved in the development of atherosclerosis, restenosis, and related fibroproliferative diseases that are prevalent in the elderly population.