APOLIPOPROTEIN E IN CHOLESTEROL TRANSPORT AND METABOLISM

载脂蛋白 E 在胆固醇运输和代谢中的作用

• 批准号: 3411042
• 负责人: ROBERT E PITAS
• 金额: $ 6.31万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3411042
• 关键词: Ceboidea; HMG coA reductases; affinity chromatography; apolipoproteins; axon; central nervous system; cerebrospinal fluid; cholesterol; dogs; electron microscopy; extracellular matrix; extracellular matrix proteins; growth factor; immunochemistry; immunocytochemistry; laboratory mouse; laboratory rabbit; laboratory rat; lipid transport; nervous system regeneration; nonblood lipoprotein; nutrition related tag; peripheral nervous system; receptor; steroid metabolism; thin layer chromatography; tissue /cell culture

A long-term goal of our laboratory is to understand the role of apolipoprotein (apo-) E in cholesterol metabolism. Apolipoprotein E is associated with various lipoproteins in the plasma. It mediates their binding to the apo-B,E(LDL) receptor, resulting in the uptake of these lipoproteins and the regulation of intracellular cholesterol metabolism. Our recent studies have suggested that apo-E also plays an important role in lipid transport and metabolism within the central and peripheral nervous systems. In addition, following injury to peripheral nerves, a dramatic increase in apo-E production is observed. The correlation of this increase with regeneration suggests a role for apo-E in the regulation of axon regrowth and remyelinization. The first aim of this proposal is to study the role of apo-E in lipid transport and cholesterol homeostasis in the nervous system. In the central nervous system we will characterize the apo-E- and apo-A-I- containing lipoproteins in cerebrospinal fluid to determine the source of their lipids. Additionally, we will determine the distribution of apo-B,E(ldl) receptors in both the central and peripheral nervous systems, as well as whether these receptors are regulated by plasma cholesterol levels. The second aim is to explore the possible role of apo-E-mediated lipid transfer during nerve regeneration. Tissue culture experiments will be used to test the importance of apo-E-containing lipoproteins and apo- B,E(LDL) receptors for axon elongation and myelinization. Additionally, a study of regenerating and nonregenerating nerve models by immunocytochemistry, electron microscopy, and biochemistry will be used to ascertain the relationship of specific cellular events to apo-E secretion, apo-B,E(LDL) receptor expression, and lipoprotein accumulation in the nerve. The in vivo levels of apo-E levels of apo-E will also be manipulated in various model systems in at attempt to modulate axon elongation or remyelinization. The third aim is to determine whether apo-E may have an effect on neural tissue that is unrelated to lipid transport and homeostasis. The effect of apo-E on the adhesion of neurons to extracellular matrix proteins or on their extension of axons in response to growth factors will be determined. Together, these studies will help elucidate the role of apo-E in normal nervous tissue and in nerve regeneration.

我们实验室的一个长期目标是了解 载脂蛋白E在胆固醇代谢中的作用。 载脂 E与血浆中的各种脂蛋白有关。 它 介导它们与apo-B，E（LDL）受体的结合，导致 这些脂蛋白的摄取和细胞内 胆固醇代谢 我们最近的研究表明， apo-E还在脂质转运中起重要作用， 中枢和外周神经系统内的代谢。 在 此外，在外周神经损伤后， 观察到apo-E产量增加。 这种关联 随着再生的增加，apo-E在再生过程中的作用 调节轴突再生和髓鞘再生。 的首要目标 本研究旨在研究apo-E在脂质转运中的作用， 胆固醇在神经系统中的稳态。 中部 神经系统我们将描述apo-E-和apo-A-I- 含有脑脊髓液中的脂蛋白， 脂肪的来源。 此外，我们将确定 apo-B，E（ldl）受体在中枢和 周围神经系统，以及这些受体是否 是由血浆胆固醇水平调节的。 第二个目标是 探讨apo-E介导的脂质转移在 神经再生 组织培养实验将用于 测试含载脂蛋白E的脂蛋白和载脂蛋白的重要性， B、E（LDL）受体用于轴突伸长和髓鞘化。 此外，再生和非再生神经的研究 免疫细胞化学，电子显微镜， 生物化学将被用来确定特定的关系， apo-E分泌的细胞事件，apo-B，E（LDL）受体 表达和脂蛋白在神经中的积累。 体内 apo-E的水平也将在各种不同的情况下被操纵。 模型系统试图调节轴突伸长或 髓鞘再生 第三个目标是确定apo-E是否 可能对神经组织产生与脂质无关的影响 运输和体内平衡。 载脂蛋白E对粘附的影响 细胞外基质蛋白或其延伸 将确定轴突对生长因子的反应。 总之，这些研究将有助于阐明apo-E在 正常神经组织和神经再生。