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

HDL受体SR-BI与冠心病模型

• 批准号: 7006134
• 负责人: MONTY KRIEGER
• 金额: $ 46.57万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006134
• 关键词: apolipoprotein E; atherosclerosis; cholesterol; coronary disorder; genetic library; genetically modified animals; high density lipoproteins; human subject; laboratory mouse; lipid transport; molecular pathology; receptor

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.

高密度脂蛋白受体，B类I型清除率受体（Sr-BI），通过选择性脂质摄取介导高密度脂蛋白胆固醇的细胞递送，这一机制不同于经典的受体介导的内吞作用。此外，SR-BI可以结合LDL和VLDL，介导非脂蛋白胆固醇的细胞摄取和刺激细胞胆固醇外排。包括肝脏过表达SR-BI和SR-BI纯合零突变体（SR-BI KO）分析在内的小鼠体内研究表明，SR-BI在1)决定血浆HDL和胆道胆固醇水平以及HDL结构方面发挥着关键作用，2)介导HDL-胆固醇向类固醇组织和肝脏的调节传递，3)保护动脉粥样硬化。在鼠饲apoE KO遗传背景下（自发性动脉粥样硬化标准小鼠模型），纯合子SR-BI KO可显著加速动脉粥样硬化。此外，这些小鼠（'dKO'）表达多种心脏传导缺陷。它们在5-7周龄之间死亡。dKO小鼠的这些独特的特性提高了它们作为人类某些形式冠心病的强大模型的可能性，为某些形式的人类冠心病提供了新的机制认识和平台，为新的治疗预防策略提供了新的机制认识和平台。这个项目的双重目标是我)的早期冠心病发病和死亡的机制在dKO老鼠,并评估的有效性dKO鼠标作为人类dKO冠心病和死亡的模型小鼠,并评估的有效性dKO鼠标作为人类的冠心病,模型和II)识别和characterize-using体细胞和分子基因细胞机械和机制SR-BI背后的深刻的对小鼠心血管系统的影响。广泛的分子、细胞、生理学、成像、遗传学、基因组学和药理学方法将与其他项目和核心设施密切配合使用。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冠心病的影响，2)我们将使用转录谱“指纹图谱”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阳性/阴性突变选择和基于逆转录病毒文库的基因克隆方法来识别细胞水平上SR-BI活性所必需的基因产物和功能。这项工作将有助于阐明心血管功能和病理生理的关键生物学机制。