Regulation of mRNA Stability in Vascular smooth Muscle

血管平滑肌 mRNA 稳定性的调节

• 批准号: 7485123
• 负责人: Mark B Taubman
• 金额: $ 42.42万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485123
• 关键词: Accounting; Adverse effects; Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Aorta; Arterial Injury; Atherosclerosis; Binding; Biology; Cultured Cells; Data; Development; Dexamethasone; Dose; Elevation; Endothelial Cells; Event; FOS gene; Gene Expression; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Half-Life; Inflammation; Inflammatory Response; Injury; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Monocyte Chemoattractant Protein-1; Platelet-Derived Growth Factor; Play; Process; Property; Protein Tyrosine Kinase; Proteins; Recruitment Activity; Regulation; Role; Serum; Signal Pathway; Smooth Muscle Myocytes; Specificity; System; Testing; Thinking; Transgenic Mice; Vascular Smooth Muscle; beta-Chemokines; cell type; chemokine; design; in vivo; insight; mRNA Stability; macrophage; monocyte; mouse model; neurotensin mimic 2; novel; novel strategies; programs; response

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中起关键作用， 动脉粥样硬化的发展。血小板源性生长因子（PDGF）是SMC的激活剂和强效诱导剂 MCP-1 PDGF对SMC中MCP-1 mRNA水平的影响主要是由于其mRNA水平的显著增加。 半衰期（t1/2）。与此相反，糖皮质激素地塞米松（Dex）抑制MCP-1 mRNA的积累， 多种细胞类型;在SMC中，这是由于mRNA t1/2显著降低。德克斯效应似乎是 依赖于糖皮质激素受体（GR），但不依赖于新的转录，提示GR的新作用。 尽管关于PDGF和Dex调节基因表达的机制有相当多的信息， 转录，但对它们对mRNA稳定性的影响知之甚少。这项建议将审查各种机制， PDGF和Dex通过其调节细胞培养和体内MCP-1 mRNA的稳定性。目标1将描述 MCP-1 mRNA的Dex敏感区，阐明Dex使MCP-1 mRNA不稳定的机制， 并鉴定相关的蛋白质。还将强调确立政府代表处在监管 MCP-1 mRNA稳定性。同样，目标2将描述PDGF增强MCP-1的机制 mRNA的稳定性，并确定所涉及的蛋白质。目的3探讨MCP-1 mRNA稳定性的调控 并将建立Dex对MCP-1介导的体内事件的影响。它还将开发 用于检测目的1和2中鉴定的MCP-1 mRNA稳定性介质的动物模型。这些研究将 为MCP-1的调节、PDGF和糖皮质激素的生物学以及 动脉壁的炎症反应。它也可能提供抑制MCP-1表达的新方法 通过模拟Dex的作用或通过阻断PDGF对MCP-1 mRNA的作用来抑制巨噬细胞增殖。