APOLIPOPROTEIN E IN CHOLESTEROL TRANSPORT AND METABOLISM

我们实验室的一个长期目标是了解 载脂蛋白E与胆固醇代谢载脂蛋白 E与血浆中的各种脂蛋白有关。它 介导它们与载脂蛋白B，E(低密度脂蛋白)受体的结合，导致 这些脂蛋白的摄取和细胞内的调节 胆固醇代谢。我们最近的研究表明 载脂蛋白-E也在脂质转运和 中枢和周围神经系统内的新陈代谢。在……里面 此外，周围神经损伤后，戏剧性的 观察到载脂蛋白E产量的增加。这其中的关联性 随着再生而增加提示载脂蛋白E在 轴突再生和再髓鞘形成的调节。的第一个目标 本研究旨在研究载脂蛋白-E在脂类转运中的作用。 神经系统中的胆固醇稳态。在中部 神经系统我们将描述apo-E-和apo-A-i- 在脑脊液中含有脂蛋白以确定 他们的脂类来源。此外，我们将确定 载脂蛋白B、E(低密度脂蛋白)受体在中枢和中脑的分布 外周神经系统，以及这些受体 受血浆胆固醇水平的调节。第二个目标是 探讨载脂蛋白E介导的脂质转移在动脉粥样硬化中的可能作用 神经再生。组织培养实验将用于 检测载脂蛋白E和载脂蛋白的重要性 B，E(低密度脂蛋白)受体与轴突延长和髓鞘形成有关。 此外，对再生神经和非再生神经的研究 通过免疫细胞化学、电子显微镜和 生物化学将被用来确定特定的 载脂蛋白E分泌、载脂蛋白B、E(低密度脂蛋白)受体的细胞事件 表达和脂蛋白在神经中的积聚。活体内 载脂蛋白E的水平也将在不同的 模型系统试图调节轴突伸长或 再髓鞘形成。第三个目标是确定载脂蛋白E是否 可能对神经组织产生与脂质无关的影响 运输和动态平衡。载脂蛋白E对粘附性的影响 从神经元到细胞外基质蛋白或它们的延伸 轴突对生长因子的反应将被确定。 总之，这些研究将有助于阐明载脂蛋白E在 正常的神经组织和神经再生。

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.