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.

高密度脂蛋白受体是B型清道夫受体I(sr-BI)，它通过选择性摄取脂质来调节细胞内高密度脂蛋白胆固醇的转运，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还能与低密度脂蛋白和极低密度脂蛋白结合，介导细胞对非脂蛋白胆固醇的摄取，并刺激细胞胆固醇外流。在小鼠体内的研究，包括肝脏SR-BI的过度表达和SR-BI纯合子缺失突变(SR-BI KO)的分析表明，SR-BI在1)决定血浆高密度脂蛋白和胆汁胆固醇水平以及高密度脂蛋白结构方面发挥关键作用，2)在调节高密度脂蛋白-胆固醇向类固醇生成组织和肝脏的运输，以及3)在防止动脉粥样硬化方面发挥关键作用。在喂食apoE KO的遗传背景(自发性动脉粥样硬化的标准小鼠模型)上，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’)表现出多种心脏传导缺陷。它们在5-7周大的时候死亡。DKO小鼠的独特特性使它们有可能成为某些形式的人类CHD的强大模型，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，为新的预防策略的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)确定dKO小鼠早发冠心病和死亡的机制，评估dKO小鼠作为人类CHD和死亡模型的有效性，以及评估dKO小鼠作为人类CHD模型的有效性，以及ii)利用体细胞和分子遗传学识别和表征SR-BI对小鼠心血管系统深刻影响的细胞机制和机制。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转基因表达对dKO CHD的影响，2)我们将使用转录图谱‘指纹’来评估疾病进展和潜在治疗干预的后果，3)我们将使用最近开发的正/负突变选择和基于逆转录病毒文库的基因克隆方法，在细胞水平上鉴定对SR-BI活性至关重要的基因产物和功能。这项拟议的工作应该有助于阐明心血管功能和病理生理学的关键生物学机制。