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===========================================

超过提供的空间。在赠款的第一个周期中，我们探讨了巨噬细胞表达的载脂蛋白E（APOE）的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之间的独特肝轴。因为LRP和APOE都在巨噬细胞中大量表达，所以我们假设该轴也在血管壁中运行，在那里它可以将内膜脂蛋白摄取到特定的细胞内路由中。具体目标1将解决巨噬细胞LRP在动脉粥样硬化中的作用。所检验的假设是LRP是ApoE在动脉壁中抗动脉粥样硬化作用的中介，其缺失将促进病变的生长。由于APOE是细胞中胆固醇外排的生理驱动力，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来介导的，胆固醇稳态涉及巨噬细胞胆固醇的摄取和处理。特定的目标2将解决由巨噬细胞表达的APOE受体结合缺陷变体对胆固醇外排和脂蛋白摄取的影响，以及它们与巨噬细胞LRP的相互作用。所检验的假设是，APOE不仅通过充当Accepter，而且还通过模拟LRP介导的脂蛋白摄取来影响体内胆固醇外排。在巨噬细胞中存在多种胆固醇外排的途径，ATP结合盒（ABC）转运蛋白和清道夫受体B1型（SR-B1）可以充当将细胞胆固醇传递到细胞外accepers的通道。 ABCA1将磷脂和胆固醇转载至ApoaI。 SR-B1通常参与肝HDL胆固醇摄取，但在巨噬细胞中，胆固醇也可以朝相反的方向流动并导致净外排。具体目标3将研究巨噬细胞中APOE介导的胆固醇外排的机制及其与ABCA1或SR-B1的关系（如果有的话）。所检验的假设是，巨噬细胞的APOE介导的胆固醇外排独立于ABCA1或SR-B1机制。表演站点=============================================================================================