Regulation of mRNA Stability in Vascular smooth Muscle

血管平滑肌 mRNA 稳定性的调节

• 批准号: 7429098
• 负责人: Mark B Taubman
• 金额: $ 41.65万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429098
• 关键词: atherosclerosis; biological models; chemical stability; corticosteroid receptors; dexamethasone; genetically modified animals; inflammation; laboratory mouse; laboratory rat; messenger RNA; monocyte chemoattractant protein 1; platelet derived growth factor; tissue /cell culture; vascular smooth muscle

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine secreted by endothelial cells, smooth muscle cells (SMC), and macrophages that plays a key role in recruiting macrophages to the arterial wall during the development of atherosclerosis. Platelet-derived growth factor (PDGF) is an activator of SMC and a potent inducer of MCP-1. The effect of PDGF on MCP-1 mRNA levels in SMC is due largely to a marked increase in mRNA half-life (t1/2). In contrast, the glucocorticoid dexamethasone (Dex) inhibits the accumulation of MCP-1 mRNA in a variety of cell types; in SMC this is due to a marked decrease in mRNA t1/2. The Dex effect appears to be dependent upon the glucocorticoid receptor (GR), but not on new transcription, suggesting a novel role for the GR. Although there is considerable information concerning the mechanisms by which PDGF and Dex regulate gene transcription, far less is known about their effects on mRNA stability. This proposal will examine the mechanisms by which PDGF and Dex regulate MCP-1 mRNA stability in cell culture and in vivo. Aim 1 will characterize the Dex-sensitive region of the MCP-1 mRNA, elucidate the mechanisms by which Dex destabilizes MCP-1 mRNA, and identify the proteins involved. Emphasis will also be placed on establishing the role of the GR in regulating MCP-1 mRNA stability. Similarly, aim 2 will characterize the mechanism by which PDGF enhances MCP-1 mRNA stability and identify the protein(s) involved. Aim 3 will examine the regulation of MCP-1 mRNA stability in animal models and will establish the effect of Dex on MCP-1-mediated events in vivo. It will also develop animal models for examining mediators of MCP-1 mRNA stability identified in aims 1 and 2. These studies will provide new insights into the regulation of MCP-1, the biology of PDGF and glucocorticoids, and the control of the inflammatory response in the arterial wall. It may also provide novel approaches to inhibiting MCP-1 expression and macrophage accumlation by mimicking the effect of Dex or by blocking the effect of PDGF on MCP-1 mRNA.

单核细胞趋化蛋白-1(MCP-1)是一种由内皮细胞、平滑肌细胞分泌的趋化因子 (SMC)和巨噬细胞，在将巨噬细胞募集到动脉壁起关键作用。 动脉粥样硬化的发展。血小板衍生生长因子(PDGF)是SMC的激活剂和强有力的诱导剂 单核细胞趋化蛋白-1。PDGF对SMC单核细胞趋化蛋白-1基因表达的影响在很大程度上是由于其基因表达显著增加 半衰期(T1/2)。相反，糖皮质激素地塞米松(Dex)抑制MCP-1mRNA的积聚。 多种细胞类型；在SMC中，这是由于mRNA T1/2显著减少。Dex效应似乎是 依赖于糖皮质激素受体(GR)，但不依赖于新的转录，提示GR具有新的作用。 尽管关于PDGF和Dex调控基因的机制有相当多的信息 转录方面，人们对它们对信使核糖核酸稳定性的影响知之甚少。这项提案将审查这些机制 通过PDGF和Dex调节MCP-1mRNA在细胞培养和体内的稳定性。目标1将描述 MCP-1mRNA的地塞米松敏感区，阐明地塞米松破坏MCP-1mRNA稳定的机制， 并确定涉及的蛋白质。此外，亦会着重确立政府物料供应处在监管方面的角色。 MCP-1mRNA的稳定性。同样，目标2将描述PDGF增强MCP-1的机制 并鉴定涉及的蛋白质(S)。目标3将研究单核细胞趋化蛋白-1mRNA稳定性的调节 在动物模型中，并将确定地塞米松对MCP-1介导的体内事件的影响。它也将发展成为 用于检测AIMS 1和AIMS 2中确定的MCP-1mRNA稳定性介体的动物模型。这些研究将 为单核细胞趋化蛋白-1的调节、血小板衍生生长因子和糖皮质激素的生物学以及血管紧张素转换酶的控制提供新的见解 动脉壁的炎症反应。它还可能提供抑制MCP-1表达的新方法 通过模仿地塞米松的作用或阻断PDGF对MCP-1mRNA的作用，促进巨噬细胞的聚集。