Regulation of vascular smooth muscle mRNA stability

描述（由申请方提供）：血管平滑肌细胞对 多种细胞外配体通过细胞表面受体起作用， 其中许多被认为是血管疾病的致病因素。 虽然这些启动复杂的细胞内信号信息流， 人们对这种复杂性是如何整合的知之甚少。受体信号是 众所周知，控制转录作用过程，而很少是 已知的控制过程，在转录后水平上发挥作用。我们 建议在解决人权问题的背景下， 信号整合我们的一般假设是， 平滑肌细胞中的转录后机制也起着重要的作用 在控制即刻早期基因表达和调节转录 机制等我们计划开发三个具体主题：i）了解在一个 系统是否有多个信号通路调节功能 转录后机制。（二）同时证明 触发的转录和转录后机制可以合作， 协同地指定由一个或多个细胞引起的立即早期mRNA反应， 刺激。㈢在确定分子因素和/或 作为反式作用剂的分子机制， 对受体信号的转录后反应。我们的四个具体 目的是：1）验证以下假设： 血管AT 1-R mRNA与一系列因子相互作用，包括 cAMP依赖性激酶信号传导的底物。2)为了验证这个假设， 丝裂原诱导的即刻早期考克斯2基因表达涉及协调 激活同时在转录和转录水平起作用的因子， 转录后水平。3)为了验证信号通路 和机制参与控制即时早期转录后 IL-6基因表达调控与考克斯2基因调控不同 诱导4)为了验证基因表达变化的假设， 酵母中蛋白偶联交配信息素途径的激活可以 涉及转录后机制。这一研究过程将阐明 VSMC表型如何整合信号转导信息， 继续在理解分子和细胞基础方面取得坚实进展， 基因表达的转录后调控。

DESCRIPTION (provided by applicant): Vascular smooth muscle cells respond to a diverse array of extracellular ligands acting through cell surface receptors, many of which have been implicated as causative factors in vascular disease. Although these initiate complex streams of intracellular signaling information, little is known about how this complexity is integrated. Receptor signaling is well known to control transcriptionally acting processes, whereas little is known about control of processes that act at the post-transcriptional level. We propose to focus on mechanisms of the latter in the context of the problem of signaling integration. Our general hypothesis is that regulated post-transcriptional mechanisms in smooth muscle cells play as important a role in controlling immediate early gene expression as do regulated transcriptional mechanisms. We plan to develop three specific themes: i) To understand in one system whether multiple signaling pathways modulate functional post-transcriptional mechanisms. ii) To demonstrate that simultaneously triggered transcriptional and post-transcriptional mechanisms can cooperate synergistically in specifying immediate-early mRNA responses evoked by a stimulus. iii) To make progress in identifying molecular factors and/or molecular mechanisms that function as trans-acting agents mediating post-transcriptional responsiveness to receptor signaling. Our four specific aims are to: 1) To test the hypothesis that the 5' untranslated region of the vascular AT1 -R mRNA interacts with a complex of factors that include substrates of cAMP-dependent kinase signaling. 2) To test the hypothesis that mitogen-induced immediate-early COX 2 gene expression involves coordinate activation of factors that simultaneously function at transcriptional and post-transcriptional levels. 3) To test the hypothesis that signaling pathways and mechanisms involved in controlling immediate-early post-transcriptional modulation of IL-6 gene expression differ from those involved in COX 2 gene induction. 4) To test the hypothesis that changes in gene expression by activation of the 0 protein-coupled mating pheromone pathway in yeast can involve post-transcriptional mechanisms. This course of research will clarify both how the VSMC phenotype integrates signal transduction information and will continue solid progress in understanding the molecular and cellular basis of post-transcriptional regulation in gene expression.