THE ATHEROPROTECTIVE EFFECTS OF SR-BI

描述(改编自《调查者摘要》)：高密度脂蛋白受体，清道夫 B型受体(SR-BI)介导细胞内高密度脂蛋白胆固醇的传递 通过选择性地摄取脂质，一种与 经典的受体介导的内吞作用(例如，低密度脂蛋白受体(LDLR)途径)。 SR-BI是一种多配体受体，可以结合低密度脂蛋白和极低密度脂蛋白，以及高密度脂蛋白。 能同时介导细胞对非脂蛋白胆固醇的摄取和细胞 胆固醇外流。它也可能与肠道胆固醇有关。 吸收。对小鼠的体内研究，包括肝脏过表达 SR-BI和SR-BI纯合零突变体(SR-BI KO)的分析表明， SR-BI在测定血浆高密度脂蛋白和胆汁中起关键作用 胆固醇和高密度脂蛋白结构，2)在调节递送中的作用 高密度脂蛋白-胆固醇对类固醇生成组织和肝脏的保护作用 在某些情况下可抗动脉粥样硬化。正常卵母细胞也需要它。 发育和女性生育能力。SR-BI的潜在机制 抗动脉粥样硬化的作用尚不清楚；然而， SR-BI/apoE双KOS显著加速动脉粥样硬化 相对于单个KO包括：i)相对量的变化 致动脉粥样硬化和抗动脉粥样硬化的胆固醇(例如，正常的高密度脂蛋白 脂蛋白，ii)改变胆固醇流入或流出血管壁的流量， 可能直接由于高密度脂蛋白结构异常或SR-BI介导的外流减少所致 来自巨噬细胞，以及iii)总体反向胆固醇转运减少， 主要是由于肝脏中SR-BI活性的丧失。的主要目标 这项提议是为了测试其中的几个假设，并进一步探索 SR-BI在胆固醇代谢中的作用这项工作将集中在组织或细胞上 动脉粥样硬化中SR-BI活性的类型特异性表达或消融 模型(apoE和LDLR KO小鼠)。我们将使用正义腺病毒和反义腺病毒 载体、基因靶向敲除(KO)小鼠和骨髓移植 控制SR-BI活性的细胞和组织特异性表达或消融， 特别关注巨噬细胞和肝脏。人血清白蛋白的体外分析 正常和SR-BI-KO巨噬细胞和/或动脉粥样硬化相关功能 将进行正常和异常的脂蛋白检查。此外，我们还将 检查SR-BI可能在肠道胆固醇中起作用的暗示 吸收。拟议中的工作将有助于阐明关键的分子和细胞 脂脂蛋白和代谢的潜在机制与动脉粥样硬化 可能会显著影响制药研究的方向和 旨在开发新的预防和预防方法的发展 动脉粥样硬化的治疗。

DESCRIPTION (Adapted from Investigator's Abstract): The HDL receptor, scavenger receptor, class B type I (SR-BI), mediates cellular delivery of HDL cholesterol by selective lipid uptake, a mechanism fundamentally different from that of classic receptor-mediated endocytosis (e.g., LDL receptor (LDLR) pathway). SR-BI is a multiligand receptor that can bind LDL and VLDL as well as HDL, and can mediate both cellular uptake of non-lipoprotein cholesterol and cellular cholesterol efflux. It may also be involved in intestinal cholesterol absorption. In vivo studies with mice, including hepatic overexpression of SR-BI and analysis of SR-BI homozygous null mutants (SR-BI KO), have shown that SR-BI plays a key role 1) in determining the levels of plasma HDL and biliary cholesterol and HDL structure, 2) in mediating the regulated delivery of HDL-cholesterol to steroidogenic tissues and the liver, and 3) in protecting against atherosclerosis in some cases. It is also required for normal oocyte development and female fertility. The mechanisms underlying SR-BI's antiatherogenic effects are unknown; however, potential causes of the dramatically accelerated atherosclerosis see in the SR-BI/apoE double Kos relative to the single Kos include: I) changes in relative amounts of cholesterol in proatherogenic and antiatherogenic (e.g., normal HDL lipoproteins, ii) altered flux of cholesterol into or out of the vessel wall, perhaps directly due to abnormal HDL structure or reduced SR-BI-mediated efflux from macrophages, and iii) decreases in overall reverse cholesterol transport, primarily due to loss of SR-BI activity in the liver. The primary goals of this proposal are to test several of these hypotheses and further explore the role of SR-BI in cholesterol metabolism. The work will focus on tissue or cell type-specific expressing or ablation of SR-BI activity in atherosclerosis models (apoE and LDLR KO mice). We will use sense and antisense adenovirus vectors, gene-targeted knockout (KO) mice, and bone marrow transplantation to control the cell and tissue-specific expression or ablation of SR-BI activity, with a special focus on macrophages and the liver. In vitro analyses of atherosclerosis-related functions of normal and SR-BI KO macrophages and or normal and abnormal lipoproteins will be performed. IN addition, we will examine the suggestions that SR-BI may play a role in intestinal cholesterol absorption. The proposed work will help elucidate key molecular and cellular mechanisms underlying lipid lipoprotein and metabolism and atherosclerosis, and may significantly influence the direction of pharmaceutical research and development aimed toward developing new methods for the prevention and treatment of atherosclerosis.