THE ATHEROPROTECTIVE EFFECTS OF SR-BI

描述（改编自研究者摘要）：HDL受体，清道夫 受体，B I型（SR-BI），介导HDL胆固醇的细胞递送 通过选择性脂质摄取，一种与 典型的受体介导的内吞作用（例如，LDL受体（LDLR）途径）。 SR-BI是可以结合LDL和VLDL以及HDL的多配体受体，并且 可以介导细胞对非脂蛋白胆固醇和细胞胆固醇的吸收 胆固醇流出 它也可能与肠道胆固醇有关 吸收 小鼠体内研究，包括肝脏过表达 SR-BI和SR-BI纯合无效突变体（SR-BI KO）的分析表明， SR-BI在1）确定血浆HDL和胆汁水平中起关键作用， 胆固醇和高密度脂蛋白结构，2）在介导的调节交付 HDL-胆固醇对类固醇生成组织和肝脏的作用，以及3）保护 抗动脉粥样硬化的药物。 正常卵母细胞也需要 发展和女性生育力。 SR-BI的潜在机制 抗动脉粥样硬化作用尚不清楚;然而，潜在的原因 在SR-BI/apoE双科斯中， 相对于单一科斯的变化包括：I） 促动脉粥样硬化和抗动脉粥样硬化中的胆固醇（例如，正常HDL 脂蛋白，ii）胆固醇流入或流出血管壁的流量改变， 可能直接由于异常HDL结构或SR-BI介导的外排减少 来自巨噬细胞，和iii）总体胆固醇逆向转运减少， 主要是由于肝脏中SR-BI活性的丧失。 的主要目标 这一建议是为了测试这些假设中的几个，并进一步探讨 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 动脉粥样硬化中SR-BI活性的类型特异性表达或消除 模型（apoE和LDLR KO小鼠）。 我们将使用正义和反义腺病毒 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除， 特别关注巨噬细胞和肝脏。 体外分析 正常和SR-BI KO巨噬细胞的动脉粥样硬化相关功能和/或 将进行正常和异常脂蛋白检查。 此外，我们将 研究SR-BI可能在肠道胆固醇中发挥作用的建议， 吸收 这项工作将有助于阐明关键的分子和细胞 脂质脂蛋白和代谢以及动脉粥样硬化的潜在机制，以及 可能会显著影响药物研究的方向， 开发旨在开发新的预防方法和 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.