REGULATION OF VASCULAR SMOOTH MUSCLE MRNA STABILITY

血管平滑肌细胞（VSMC）群体经历重排 从正常的收缩状态到病理状态， 动脉粥样硬化和高血压等疾病。不言而喻 基因表达模式的改变不仅伴随着这一点， 是疾病血管重塑过程的内在因素 图片 出现了一种基因， 功能被下调，并被那些更支持 增殖或病理状态。 然而， 关于调节VSMC基因表达变化的机制 模式，或者这是否代表一个精心编排的过程。 持续或不对称地暴露于多种细胞外 因子，包括生长因子、细胞因子、脂质、激素和 神经递质，已经涉及VSMC功能障碍。 这 该项目将探索在何种程度上不同的细胞外信号可能 共享共同的分子机制来下调 血管平滑肌细胞收缩功能基因。 本项目中的模型系统 是血管重塑过程的缩影 它涉及到培养 血管平滑肌细胞和检查的分子机制，负责 细胞外信号诱导的mRNA编码的不稳定， 血管紧张素II AT 1受体（AT 1-R），作为一种原型收缩剂， 基因 AT 1-R mRNA被代表性的生长因子破坏稳定， 通过激素和cAMP升高剂，所有这些都是预防性的， 转录偶联过程，这表明一个因素（S） 是诱导来调解的。 本研究的目的是：（1） 确定一个共同的信号通路是否整合了AT 1-R mRNA的衰变 由不同种类的细胞外因子诱导; 2）建立 AT 1-R mRNA分子中使其不稳定所必需的元件 为了了解特定mRNA的机制， 这一不稳定过程的目标; 3）以确定在何种程度上 AT 1-R mRNA去稳定信号改变mRNA的翻译， 确定AT 1-R mRNA翻译在其失稳过程中的作用; 4） 分离和克隆记录的AT 1-R mRNA结合蛋白， 细胞外信号，作为潜在的候选因子参与VSMC mRNA不稳定。 最先进的分子遗传学方法 将被用于操纵VSMC基因表达。

Vascular smooth muscle cell (VSMC) populations undergo rearrangements from normal, contractile to pathological states in the course of diseases such as atherosclerosis and hypertension. It is self-evident that altered gene expression patterning not only accompanies this, but is intrinsic to the vascular remodeling process of disease. A picture has emerged in which genes typically associated with contractile function are down-regulated and replaced by those more supportive of a proliferative or pathological state. However, very little is known about mechanisms that regulate these shifts in VSMC gene expression patterns, or whether this represents an orchestrated process. Persistent or skewed exposure to a diverse array of extracellular factors, including growth factors, cytokines, lipids, hormones and neurotransmitters, have been implicated in VSMC dysfunction. This project will explore to what extent diverse extracellular signals may share common molecular mechanisms to down-regulate the expression of contractile- function genes in VSMC. The model system in this project is a microcosm of the vascular remodeling process. It involves cultured VSMC and an examination of the molecular mechanisms responsible for extracellular signal-induced destabilization of the mRNA encoding the angiotensin II AT1-receptor (AT1-R), serving as a prototypic contractile gene. That AT1-R mRNA is destabilized by representative growth factors, by hormones and cAMP-elevating agents, all in a translationally- and transcriptionally-coupled process, which suggests that a factor(s) is(are) induced to mediate this. The aims of this study are: 1) to determine if a common signaling pathway integrates AT1-R mRNA decay induced by diverse classes of extracellular factors; 2) to establish the elements in the AT1-R mRNA molecule necessary for its destabilization in order to understand mechanisms for how specific mRNA's might be targeted by this destabilization process; 3) to determine to what extent AT1-R mRNA destabilizing signals alter translation of the mRNA and to establish the orle of AT1-R mRNA translation in its destabilization; 4) to isolate and clone documented AT1-R mRNA binding proteins induced by extracellular signals, as potential candidate factors involved in VSMC mRNA destabilization. State-of-the-art molecular genetic approaches will be exploited to manipulate VSMC gene expression.