MACROPHAGE CHOLESTEROL METABOLISM AND APO-E SYNTHESIS

巨噬细胞胆固醇代谢和 APO-E 合成

• 批准号: 2219286
• 负责人: THEODORE MAZZONE
• 金额: $ 10.76万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2219286
• 关键词: DNA footprinting; apolipoproteins; blood lipoprotein; blood lipoprotein biosynthesis; cell differentiation; cholesterol; electroporation; gel mobility shift assay; gene deletion mutation; genetic regulation; genetic regulatory element; human subject; laboratory mouse; laboratory rabbit; lipids; macrophage; molecular cloning; molecular genetics; monocyte; northern blottings; posttranscriptional RNA processing; posttranslational modifications; steroid metabolism; structural genes; tissue /cell culture; transcription factor

Apolipoprotein E (apoE) is synthesized and secreted by a wide variety of mammalian cells and a number of hypotheses have been developed regarding the potential functions of apoE synthesized in extrahepatic tissues. The macrophage was the first extrahepatic cell type in which apoE synthesis was reported and a great deal of information has been developed characterizing the regulation of apoE synthesis in these cells. We have been primarily interested in further exploring the mechanisms for the regulation of macrophage apoE production. In this application, we propose experiments designed to a) define the molecular mechanism for the induction of apoE gene transcription which i) accompanies cholesterol loading of macrophages; ii) accompanies differentiation of monocytes to macrophages; and b) examine post-transcriptional and post-translational regulation of apoE in macrophages and specifically, to determine how this step is modulated in response to differentiation and extracellular lipids. Our laboratory has been involved in making important basic observations for each of the experimental directions outlined above. Macrophages are a major source of apoE in extrahepatic tissues. A role for apoE has been established in participating in tissue lipid transport as well as modulating the growth, phenotype and differentiated function of a diverse group of extrahepatic cells (e.g. lymphocytes, steroidogenic cells, and mesenchymal cells). Understanding the regulation of apoE production in macrophages could provide major insights into understanding the pathophysiology of disease processes in which macrophages play a key role, for example, atherosclerosis.

载脂蛋白E（APOE）由多种多样的 关于哺乳动物细胞和许多关于 APOE在肝外组织中合成的潜在功能。 这 巨噬细胞是肝外部细胞类型的第一种APOE合成 报道了大量信息 表征这些细胞中APOE合成的调节。 我们有 主要有兴趣进一步探索 巨噬细胞APOE产生的调节。 在此应用程序中，我们 提出了旨在a）定义分子机制的实验 诱导APOE基因转录，i）伴有胆固醇 巨噬细胞的负载； ii）伴随单核细胞的分化 巨噬细胞； b）检查转录后和翻译后 巨噬细胞中APOE的调节，具体来说，以确定如何 响应分化和细胞外的步骤调节 脂质。 我们的实验室参与了重要的基本 上面概述的每个实验方向的观察结果。 巨噬细胞是肝外组织中APOE的主要来源。 角色 因为APOE已建立参与组织脂质运输的 以及调节生长，表型和分化功能 多种肝外细胞（例如淋巴细胞，类固醇生成 细胞和间质细胞）。 了解APOE的调节 巨噬细胞的生产可以为理解提供主要见解 巨噬细胞发挥关键的疾病过程的病理生理学 角色，例如动脉粥样硬化。