REGULATION OF VASCULAR SMOOTH MUSCLE MRNA STABILITY

血管平滑肌细胞群发生重排 从正常、收缩到病理状态 动脉粥样硬化和高血压等疾病。这是不言而喻的 这种改变的基因表达模式不仅伴随着这一点，而且 是疾病血管重塑过程中固有的。一张照片 已经出现了通常与收缩相关的基因 功能被下调，并被那些更支持 增殖性或病理性状态。然而，人们对此知之甚少。 关于调节VSMC基因表达的这些变化的机制 模式，或者这是否代表一个经过编排的流程。 持续或倾斜地暴露于不同的细胞外阵列 因子，包括生长因子、细胞因子、脂质、激素和 神经递质被认为与VSMC功能障碍有关。这 该项目将探索不同的细胞外信号在多大程度上可能 具有共同的下调基因表达的分子机制 血管平滑肌细胞中的收缩功能基因。本项目中的模型系统 是血管重塑过程的一个缩影。它涉及到有修养的人 VSMC及其致病分子机制的研究 细胞外信号诱导编码该基因的信使核糖核酸失稳 血管紧张素II AT1受体(AT1-R)，作为收缩的原型 吉恩。AT1-R基因被具有代表性的生长因子破坏了稳定性， 通过荷尔蒙和提升阵营的药物，所有这些都在翻译上-和 转录耦合过程，这表明一个因素(S) 是被诱导来调解这件事的。本研究的目的是：1) 确定共同的信号通路是否整合了AT1-R mRNA的衰变 由不同种类的细胞外因子诱导；2)建立 AT1-R mRNA分子中导致其失稳所必需的元件 为了了解信使核糖核酸的特异性机制 这一不稳定进程的目标；3)确定在多大程度上 AT1-R mRNA的不稳定信号改变了该mRNA的翻译，并 建立AT1-R mRNA翻译的失稳机制；4) 分离和克隆已记录的AT1-Rm RNA结合蛋白 细胞外信号作为参与VSMC的潜在候选因素 信使核糖核酸不稳定。最新的分子遗传学方法 将被利用来操纵VSMC基因的表达。

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.