Cell Biology of ABCA1

ABCA1 的细胞生物学

• 批准号: 6620864
• 负责人: MASON W FREEMAN
• 金额: $ 38.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620864
• 关键词: Tangier disease; apolipoproteins; binding sites; cell biology; cholesterol; clinical research; gene mutation; human genetic material tag; ligands; lipid transport; membrane transport proteins; molecular pathology; posttranslational modifications; protein localization; protein structure function

The control of intra-cellular cholesterol levels is an intricately regulated process that depends not only on the regulation of lipid uptake and cellular sterol synthesis but also on a mechanism that permits cells to efflux cholesterol to apolipoprotein and lipoprotein acceptor molecules. The best evidence for the importance of this efflux pathway in human physiology comes from studies of patient's with Tangier disease. Recent work has shown that the genetic defect in Tangier disease maps to a locus encoding a member of the ABCA family of ATP- binding cassette transporters (ABCA1) and that this transporter is required for normal, apolipoprotein-stimulated cholesterol efflux. In vivo, the reverse cholesterol transport pathway is thought to be initiated when a lipid-poor HDL binds to a cell and stimulates the removal of cellular lipids, at least in part, via this ABCA1-mediated process. As the pharmacologic tools for manipulating the reverse cholesterol transport pathway are far less sophisticated and effective than those available for reducing the levels of pro-atherogenic lipoproteins, insights gained from investigating ABCA1's function have the potential to lead to new clinical therapeutics. In this proposal, the investigators will explore the structural requirements that underlie ABCA1 function, focusing on its membrane topology, binding interaction with ligands, and regulation by kinases. These studies of the cell biology of the ABCA1 transporter will importantly contribute not only to a molecular description of the cellular cholesterol efflux pathway but also to our growing understanding of the mechanisms by which human cholesterol homeostasis is maintained or goes awry.

细胞内胆固醇水平的控制是一个复杂的调节过程，不仅取决于脂质摄取和细胞甾醇合成的调节，还取决于允许细胞将胆固醇流出至载脂蛋白和脂蛋白受体分子的机制。 这种外流途径在人类生理学中的重要性的最佳证据来自对丹吉尔病患者的研究。最近的研究表明，丹吉尔病的遗传缺陷映射到编码 ATP 结合盒转运蛋白 ABCA 家族 (ABCA1) 成员的基因座，并且该转运蛋白是正常的载脂蛋白刺激的胆固醇流出所必需的。 在体内，当缺乏脂质的 HDL 与细胞结合并刺激细胞脂质的去除（至少部分通过这种 ABCA1 介导的过程）时，反向胆固醇转运途径被认为是启动的。 由于操纵反向胆固醇转运途径的药理学工具远不如那些可用于降低促动脉粥样硬化脂蛋白水平的药理学工具复杂和有效，因此从研究 ABCA1 功能中获得的见解有可能带来新的临床治疗方法。 在本提案中，研究人员将探索 ABCA1 功能的结构要求，重点关注其膜拓扑、与配体的结合相互作用以及激酶的调节。这些对 ABCA1 转运蛋白细胞生物学的研究不仅将重要地有助于细胞胆固醇流出途径的分子描述，而且将有助于我们不断加深对人类胆固醇稳态维持或出错的机制的理解。