Functional Hierarchy of Remnant Lipoprotein Receptors

残余脂蛋白受体的功能层次

• 批准号: 6840855
• 负责人: SERGIO FAZIO
• 金额: $ 37.75万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6840855
• 关键词: antiatherogenic agent; apolipoprotein E; atherosclerosis; blood lipoprotein metabolism; bone marrow transplantation; cholesterol; enzyme linked immunosorbent assay; flow cytometry; gene targeting; genetically modified animals; immunocytochemistry; laboratory mouse; low density lipoprotein receptor; macrophage; membrane transport proteins; peroxisome proliferator activated receptor; protein protein interaction; protein structure function; protein transport; receptor binding; receptor expression; scavenger receptor; southern blotting

EXCEED THE SPACE PROVIDED. During the first cycle of the grant we explored the mechanisms underlying the anti-atherogenic effects of apolipoprotein E (apoE) expressed by macrophages, and delineated a unique hepatic axis between LDL receptor (LDLR) related protein (LRP) and apoE. Because both LRP and apoE are abundantly expressed in the macrophage, we postulate that this axis is operational in the vessel wall as well, where it may direct the uptake of intimal lipoproteins to a specific intracellular routing. Specific aim 1 will address the role of macrophage LRP in atherogenesis. The hypothesis tested is that LRP is the mediator of the anti-atherogenic effects of apoE in the artery wall, and that its deletion will promote lesion growth. Because apoE is a physiologic driver of cholesterol efflux from cells, its anti-atherogenic effects may be mediated by a more complex regulation of cholesterol homeostasis involving both uptake and disposition of macrophage cholesterol. Specific aim 2 will address the effects of apoE receptor binding defective variants expressed by the macrophage on cholesterol efflux and lipoprotein uptake, as well as their interaction with macrophage LRP. The hypothesis tested is that apoE affects cholesterol efflux in vivo not only by acting as an accepter but also by simulating LRP-mediated lipoprotein uptake. Multiple pathways to cholesterol efflux are present in macrophages, and the ATP-binding cassette (ABC) transporters and the scavenger receptor type B1 (SR-B1) can act as channels that deliver cellular cholesterol to extracellular accepters. ABCA1 transposes phospholipids and cholesterol to apoAI. SR-B1 is normally involved in hepatic HDL cholesterol uptake, but in the macrophage cholesterol can also flow in the opposite direction and result in net efflux. Specific aim 3 will study the mechanism of apoE-mediated cholesterol efflux from macrophages and its relationship, if any, with either ABCA1 or SR-B1. The hypothesis tested is that apoE-mediated cholesterol efflux from macrophages is independent from ABCA1 or SR-B1 mechanisms. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。在资助的第一个周期中，我们探索了巨噬细胞表达的载脂蛋白 E (apoE) 抗动脉粥样硬化作用的机制，并描绘了 LDL 受体 (LDLR) 相关蛋白 (LRP) 和 apoE 之间独特的肝轴。由于 LRP 和 apoE 在巨噬细胞中大量表达，因此我们推测该轴也在血管壁中发挥作用，它可以将内膜脂蛋白的摄取引导至特定的细胞内路线。具体目标 1 将解决巨噬细胞 LRP 在动脉粥样硬化形成中的作用。测试的假设是，LRP 是动脉壁中 apoE 抗动脉粥样硬化作用的介体，其缺失将促进病变生长。由于 apoE 是胆固醇从细胞流出的生理驱动因素，因此其抗动脉粥样硬化作用可能是通过更复杂的胆固醇稳态调节介导的，涉及巨噬细胞胆固醇的摄取和处置。具体目标 2 将解决巨噬细胞表达的 apoE 受体结合缺陷变体对胆固醇流出和脂蛋白摄取的影响，以及它们与巨噬细胞 LRP 的相互作用。测试的假设是，apoE 不仅通过充当受体，而且还通过模拟 LRP 介导的脂蛋白摄取来影响体内胆固醇流出。巨噬细胞中存在多种胆固醇流出途径，ATP 结合盒 (ABC) 转运蛋白和 B1 型清道夫受体 (SR-B1) 可以充当将细胞胆固醇传递至细胞外受体的通道。 ABCA1 将磷脂和胆固醇转变成 apoAI。 SR-B1 通常参与肝脏 HDL 胆固醇的摄取，但在巨噬细胞中胆固醇也可以沿相反方向流动并导致净流出。具体目标 3 将研究 apoE 介导的巨噬细胞胆固醇流出的机制及其与 ABCA1 或 SR-B1 的关系（如果有）。测试的假设是 apoE 介导的巨噬细胞胆固醇流出独立于 ABCA1 或 SR-B1 机制。表演网站==========================================章节结束===============================================