Functional Hierarchy of Remnant Lipoprotein Receptors

超出提供的空间。在第一轮赠款中，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，并描绘了低密度脂蛋白受体(LDLR)相关蛋白(LRP)和apoE之间独特的肝轴。因为LRP和apoE在巨噬细胞中大量表达，我们推测这个轴在血管壁也是可操作的，在那里它可能引导内膜脂蛋白的摄取到特定的细胞内路线。具体目标1将阐述巨噬细胞LRP在动脉粥样硬化形成中的作用。假设LRP是载脂蛋白E在动脉壁抗动脉粥样硬化作用的中介，其缺失将促进病变的生长。由于载脂蛋白E是胆固醇从细胞外流的生理驱动力，其抗动脉粥样硬化的作用可能是通过更复杂的胆固醇稳态调节来实现的，包括巨噬细胞胆固醇的摄取和处置。具体目标2将阐述巨噬细胞表达的载脂蛋白E受体结合缺陷变体对胆固醇外流和脂蛋白摄取的影响，以及它们与巨噬细胞LRP的相互作用。实验假设apoE不仅通过作为受体影响体内胆固醇外流，而且还通过模拟LRP介导的脂蛋白摄取来影响胆固醇外流。巨噬细胞中存在多种胆固醇外流途径，三磷酸腺苷结合盒(ABC)转运体和清道夫受体B1(SR-B1)可以作为通道将细胞内的胆固醇输送到细胞外受体。ABCA1将磷脂和胆固醇转位为载脂蛋白AI。SR-B1通常参与肝脏高密度脂蛋白的摄取，但在巨噬细胞中，胆固醇也可以反向流动，导致净流出。具体目标3将研究载脂蛋白E介导的胆固醇从巨噬细胞流出的机制及其与ABCA1或SR-B1的关系(如果有的话)。假设apoE介导的胆固醇从巨噬细胞流出是独立于ABCA1或SR-B1机制的。表演网站========================================Section End===========================================

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