Regulation of mRNA stability in vascular smooth muscle

血管平滑肌 mRNA 稳定性的调节

• 批准号: 6815440
• 负责人: Mark B Taubman
• 金额: $ 39万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-06 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6815440
• 关键词: atherosclerosis; chemical stability; chemical structure function; chemokine; corticosteroid receptors; dexamethasone; disease /disorder model; genetic regulation; genetically modified animals; glucocorticoids; hormone regulation /control mechanism; intracellular transport; laboratory mouse; laboratory rat; macrophage; macrophage inflammatory proteins; messenger RNA; monocyte chemoattractant protein 1; nucleic acid structure; platelet derived growth factor; posttranscriptional RNA processing; protein structure function; tissue /cell culture; transcription factor; vascular smooth muscle

DESCRIPTION (provided by applicant): 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 (tl/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 tl/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 accumulation by mimicking the effect of Dex or by blocking the effect of PDGF on MCP- 1 mRNA.

描述（申请人提供）：单核细胞趋化蛋白-1 (MCP-1) 是一种由内皮细胞、平滑肌细胞 (SMC) 和巨噬细胞分泌的趋化因子，在动脉粥样硬化发展过程中在将巨噬细胞募集到动脉壁方面发挥着关键作用。血小板衍生生长因子 (PDGF) 是 SMC 的激活剂和 MCP-1 的有效诱导剂。 PDGF 对 SMC 中 MCP-1 mRNA 水平的影响很大程度上是由于 mRNA 半衰期 (tl/2) 显着增加。相比之下，糖皮质激素地塞米松 (Dex) 可抑制多种细胞类型中 MCP-1 mRNA 的积累；在 SMC 中，这是由于 mRNA tl/2 显着减少所致。 Dex 效应似乎依赖于糖皮质激素受体 (GR)，但不依赖于新的转录，这表明 GR 具有新的作用。尽管关于 PDGF 和 Dex 调节基因转录的机制有大量信息，但关于它们对 mRNA 稳定性的影响却知之甚少。该提案将研究 PDGF 和 Dex 在细胞培养物和体内调节 MCP-1 mRNA 稳定性的机制。目标 1 将表征 MCP-1 mRNA 的 Dex 敏感区域，阐明 Dex 使 MCP-1 mRNA 不稳定的机制，并鉴定所涉及的蛋白质。重点还将放在确定 GR 在调节 MCP-1 mRNA 稳定性中的作用。同样，目标 2 将描述 PDGF 增强 MCP-1 mRNA 稳定性的机制并鉴定相关蛋白质。目标 3 将检查动物模型中 MCP-1 mRNA 稳定性的调节，并确定 Dex 对 MCP-1 介导的体内事件的影响。它还将开发动物模型来检查目标 1 和 2 中确定的 MCP-1 mRNA 稳定性介质。这些研究将为 MCP-1 的调节、PDGF 和糖皮质激素的生物学以及动脉壁炎症反应的控制提供新的见解。它还可以通过模仿 Dex 的作用或通过阻断 PDGF 对 MCP-1 mRNA 的作用来抑制 MCP-1 表达和巨噬细胞积累。