HDL receptor SR-BI and a model of coronary heart disease

HDL受体，I型B类清道夫受体（Sr-BI），通过选择性脂质摄取介导HDL胆固醇的细胞递送，这是一种不同于经典受体介导的内吞作用的机制。此外，SR-BI可以结合LDL和VLDL，并且可以介导非脂蛋白胆固醇的细胞摄取和刺激细胞胆固醇流出。对小鼠的体内研究，包括SR-BI的肝脏过表达和SR-BI纯合无效突变体（SR-BI KO）的分析，已经表明SR-BI在以下方面起关键作用：1）确定血浆HDL和胆汁胆固醇的水平以及HDL结构，2）介导HDL-胆固醇向类固醇生成组织和肝脏的调节递送，以及3）保护免受动脉粥样硬化。在一个喂食食物的apoE KO遗传背景下（自发性动脉粥样硬化的标准鼠模型），纯合子SR-BI KO导致动脉粥样硬化显著加速。此外，这些小鼠（“dKO”）表达多种心脏传导缺陷。它们在5-7周大时死亡。dKO小鼠的独特性质提高了它们可能作为某些形式的人类CHD的强大模型的可能性，为某些形式的人类CHD提供了新的机制见解和初步模型平台，为预防策略的新治疗提供了新的机制见解和初步分析平台。该项目的双重目标是：I）表征dKO小鼠早发CHD和死亡的潜在机制，并评估dKO小鼠作为人CHD和dKO小鼠死亡模型的有效性，并评估dKO小鼠作为人CHD模型的有效性，和II）使用体细胞和分子遗传学来鉴定和表征作为SR基础的细胞机器和机制，BI对小鼠心血管系统的深远影响。一系列广泛的分子、细胞、生理、成像、遗传、基因组和药理学方法将与其他项目和核心设施密切结合使用。例如，1）我们将评估病毒介导的心脏特异性转基因表达对dKO CHD的影响，2）我们将使用转录谱“指纹”来评估疾病进展和潜在治疗干预的后果，3）我们将采用最近开发的正/负突变体选择和基于逆转录病毒文库的基因克隆方法来鉴定SR-1所必需的基因产物和功能。细胞水平的BI活性。这项工作将有助于阐明心血管功能和病理生理学的关键生物学机制。

The HDL receptor, scavenger receptor Class B type I (Sr-BI), mediates cellular delivery of HDL cholesterol by selective lipid uptake, a mechanism distinct from classic receptor-mediated endocytosis. In addition, SR-BI can bind LDL and VLDL and can mediate both cellular uptake of non-lipoprotein cholesterol and stimulate cellular cholesterol efflux.. In vivo studies with mice, including hepatic over-expression 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. On a chow-fed apoE KO genetic background (standard murine model of spontaneous atherosclerosis), homozygous SR-BI KO causes dramatically accelerated atherosclerosis.. In addition, these mice ('dKO') express multiple cardiac conduction defects. They die between 5-7 weeks of age. The unique properties of the dKO mice raise the possibility that they may serve as a powerful model for some forms of human CHD, providing new mechanistic insight and a platform for preliminary model for some forms of human CHD, providing new mechanistic insights and a platform for preliminary analysis for new treatment of prevention strategies. The twin goals of this Project are I) to characterize the mechanisms underlying early onset CHD and death in dKO mice, and to assess the validity of the dKO mouse as a model for human CHD and death in dKO mice, and to assess the validity of the dKO mouse as a model for human CHD, and II) to identify and characterize-using somatic cell and molecular genetics-the cellular machinery and mechanisms which underlie SR-BI's profound effects on the murine cardiovascular system. A wide array of molecular, cellular, physiologic, imaging, genetic, genomic and pharmacologic approaches will be used in close conjunction with the other Projects and Core Facilities. For example, 1) we will evaluate the influences on dKO CHD of virus-mediated cardiac-specific transgene expression, 2) we will use transcription profile 'fingerprinting' to assess disease progression and the consequences of potential therapeutic interventions, and 3) we will employ recently developed positive/negative mutant selections and retrovirus library-based gene cloning methods to identify gene products and functions essential for SR-BI activity at the cellular level. The proposed work should help elucidate key biological mechanisms underlying cardiovascular function and pathophysiology.