CLASS B SCAVENGER RECEPTORS AND FOAM CELL FORMATION

描述（改编自研究者摘要）： 负载胆固醇的泡沫细胞是动脉粥样硬化形成中的关键事件。泡沫细胞 形成被认为是由于不受调节的受体介导的摄取 氧化脂蛋白，但涉及脂蛋白受体的身份 以及它们在体内病变发展中的重要性尚不清楚。B类 清道夫受体CD 36和SR-BI都结合氧化LDL（oxLDL），发现于 动脉粥样硬化病变和巨噬细胞，似乎是上调 oxLDL。在这个建议中要检验的中心假设是， B类清道夫受体CD 36和SR-BI在免疫调节中起重要的互补作用。 刺激巨噬细胞泡沫细胞的形成， 来自氧化脂蛋白的调节性氧化胆固醇酯， 刺激脂蛋白摄取。 具体目的1：评估巨噬细胞CD 36和SR-BI在摄取 氧化脂蛋白中的调节性氧化胆固醇酯。这将 通过研究巨噬细胞对氧化脂质的摄取， i）内吞摄取的定量重要性 CD 36和SR-BI介导的内化中的选择性脂质摄取途径 氧化胆固醇酯从oxLDL和ii）的效率， oxLDL和HDL通过CD-36和SR-BI将氧化胆固醇酯递送至细胞。 具体目标2：确定SR-BI和CD 36的调节程度 巨噬细胞中的PPAR-gamma活化和氧化脂蛋白摄取。这将 通过研究SR-BI-和CD 36-介导的PPAR-gamma活化， 氧化脂质和两种B类清除剂的后续调节 在培养的巨噬细胞中的受体。SR-BI介导的程度 PPAR-gamma激活和通过氧化的摄取的CD 36上调 脂质和SR-BI本身受到正反馈的程度 将定量评估氧化脂质的控制。 具体目的3：确定巨噬细胞特异性表达 B类清道夫受体在动脉粥样硬化病变发展中的作用 小鼠 巨噬细胞表达B类清道夫受体对泡沫形成的影响 细胞形成和血管脂质沉积将在缺乏 i）骨髓移植（BMT）， CD 36或SR-BI缺陷细胞（来源于敲除小鼠）转化为LDLR-/- 和ii）将CD 36或SR-BI过表达（通过逆转录病毒基因转移）到 LDLR-/-小鼠。动脉粥样硬化的程度将通过病变大小来量化 和胆固醇/胆固醇酯含量。

DESCRIPTION(Adapted from Investigator's Abstract): The formation of cholesterol-loaded foam cells is a key event in atherogenesis. Foam cell formation is thought to be due to the unregulated receptor-mediated uptake of oxidized lipoproteins, but the identity of the lipoprotein receptors involved and their importance in lesion development in vivo are unclear. The class B scavenger receptors CD36 and SR-BI both bind oxidized LDL (oxLDL), are found in atherosclerotic lesions and in macrophages, and appear to be up regulated by oxLDL. The central hypothesis to be examined in this proposal is that the Class B scavenger receptors, CD36 and SR-BI, play important complementary roles in stimulating macrophage foam cell formation through their efficient uptake of regulatory oxidized cholesterol esters from oxidized lipoproteins and stimulation of lipoprotein uptake. Specific Aim 1: To assess the roles of macrophage CD36 and SR-BI in the uptake of regulatory oxidized cholesterol esters from oxidized lipoproteins. This will be accomplished by studying macrophage uptake of oxidized lipids from lipoproteins and determining i) the quantitative importance of endocytic uptake and selective lipid uptake pathways in CD36- and SR-BI-mediated internalization of oxidized cholesterol esters from oxLDL and ii) the efficiencies with which oxLDL and HDL deliver oxidized cholesterol esters to cells via CD-36 and SR-BI. Specific Aim 2: To determine the extent to which SR-BI and CD36 regulate PPAR-gamma activation and oxidized lipoprotein uptake in macrophages. This will be achieved by studying SR-BI- and CD36-mediated activation of PPAR-gamma by oxidized lipids and the consequent regulation of the two Class B scavenger receptors in cultured macrophages. The extent to which SR-BI mediates PPAR-gamma activation and CD36 up regulation through the uptake of oxidized lipids and the extent to which SR-BI itself is subject to positive feedback control by oxidized lipids will be quantitatively assessed. Specific Aim 3: To determine the influence of macrophage-specific expression of Class B scavenger receptors on the development of atherosclerotic lesions in mice. The influence of macrophage expression of class B scavenger receptors on foam cell formation and vascular lipid deposition will be studied in the absence of confounding changes in lipoproteins by i) bone marrow transplantation (BMT) of cells deficient in CD36 or SR-BI (derived from knock-out mice) into LDLR-/- mice and ii) over-expressing CD36 or SR-BI (by retroviral gene transfer) into LDLR-/- mice. The extent of atherosclerosis will be quantified by lesion size and cholesterol/cholesterol ester content.