Cell Biology of ABCA1

细胞内胆固醇水平的控制是一个复杂的调控过程，它不仅依赖于脂质摄取和细胞固醇合成的调控，而且还依赖于一种允许细胞将胆固醇外排到载脂蛋白和脂蛋白受体分子的机制。这种外排途径在人体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定位于一个编码ATP结合盒转运蛋白（ABCA1） ABCA家族成员的位点，该转运蛋白是正常的、载脂蛋白刺激的胆固醇外排所必需的。在体内，当脂质贫乏的HDL与细胞结合并刺激细胞脂质的去除时，逆向胆固醇转运途径被认为是启动的，至少部分是通过abca1介导的过程。由于操纵逆向胆固醇转运途径的药理学工具远不如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，研究ABCA1功能获得的见解有可能导致新的临床治疗方法。在本研究中，研究人员将探索ABCA1功能背后的结构要求，重点关注其膜拓扑结构、与配体的结合相互作用以及激酶的调节。这些关于ABCA1转运体的细胞生物学研究将不仅对细胞胆固醇外排途径的分子描述做出重要贡献，而且对我们越来越多地了解人类胆固醇稳态维持或出错的机制也有重要贡献。

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.