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.

HDL受体，清道夫受体B类I类（SR-BI）通过选择性脂质摄取介导HDL胆固醇的细胞递送，这是一种与经典受体介导的内吞作用不同的机制。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并刺激细胞胆固醇外排..在体内研究。在体内研究，包括SR-BI的肝过表达SR-BI和SR-BI的分析和SR-BI型型纯度杂物（SR）play sr 1 pl sr sr sr a ke in ke sr a inding a ke in ke in ke in ke sr in ke in ke sr in ke sr a ki ke in ke sr a in ke sr in ke in ke sr a ki kie sr in ke sr a in are pli血浆HDL和胆汁胆固醇和HDL结构，2）在介导HDL-胆固醇向类固醇组织和肝脏的调节递送时，以及3）保护动脉粥样硬化。在杂烩喂养的Apoe KO遗传背景（自发动脉粥样硬化的标准鼠模型）上，纯合SR-BI KO会导致动脉粥样硬化加速。他们在5-7周龄之间死亡。 DKO小鼠的独特特性增加了它们可以作为某些形式的人类冠心病的强大模型，为某些形式的人类冠心病提供了新的机械洞察力，并为人们提供了新的机械洞察力，并为预防策略提供新的治疗策略的初步分析。 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对鼠心血管系统的深刻影响。将与其他项目和核心设施密切相结合，将多种分子，细胞，生理，遗传，基因组和药理学方法与其他分子，生理成像，遗传，基因组和药理学方法一起使用。 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.提出的工作应有助于阐明心血管功能和病理生理学基础的关键生物学机制。