Regulation of vascular smooth muscle mRNA stability

描述(申请人提供)：血管平滑肌细胞对 不同的细胞外配体通过细胞表面受体发挥作用， 其中许多已被认为是血管疾病的致病因素。 尽管这些启动了复杂的细胞内信令信息流， 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，它能控制转录作用过程，而很少有人能做到 已知在转录后水平上对过程的控制。我们 建议将重点放在后一种机制的问题上 信令集成。我们的普遍假设是，受监管的 在平滑肌细胞中，转录后机制起着重要作用 在控制即刻早期基因表达方面与受调控的转录 机械装置。我们计划开发三个具体的主题：i)在一个 系统是否有多条信号通路调节功能 转录后机制。二)同时证明 触发的转录和转录后机制可以协同 协同作用，指定由一种基因引起的即刻-早期信使核糖核酸反应 刺激。三)在确定分子因素和/或 作为反式作用介质发挥作用的分子机制 转录后对受体信号的反应。我们的四个特例 目的是：1)检验假设，5‘非翻译区的 血管AT1-R mRNA与多种因子相互作用，包括 CAMP依赖的激酶信号的底物。2)检验假设 丝裂原诱导的即刻-早期COX-2基因表达涉及协调 激活同时在转录和转录水平上起作用的因子 转录后水平。3)检验信号通路的假设 和控制即刻-早期转录后转录的机制 IL-6基因表达的调控不同于COX-2基因的调控 归纳法。4)检验通过以下方式改变基因表达的假设 酵母中0蛋白偶联交配信息素途径的激活 涉及转录后机制。这门研究课程将阐明 VSMC表型如何整合信号转导信息和将 继续在理解人类免疫缺陷病毒的分子和细胞基础方面取得扎实进展 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.