Cell Biology of ABCA1

细胞内胆固醇水平的控制是一个复杂的调节过程，不仅取决于脂质摄入和细胞固醇合成的调节，还取决于允许细胞将胆固醇外排至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映射到编码ATP结合盒转运蛋白（ABCA 1）的ABCA家族成员的基因座，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，胆固醇逆向转运途径被认为是在贫脂HDL结合细胞并刺激细胞脂质去除时启动的，至少部分是通过ABCA 1介导的过程。 由于用于操纵胆固醇反向转运途径的药理学工具远不如用于降低促动脉粥样硬化脂蛋白水平的那些工具复杂和有效，因此从研究ABCA 1的功能中获得的见解有可能导致新的临床治疗。 在这项提案中，研究人员将探索ABCA 1功能的结构要求，重点是其膜拓扑结构，与配体的结合相互作用以及激酶的调节。这些ABCA 1转运蛋白的细胞生物学研究将不仅对细胞胆固醇流出途径的分子描述做出重要贡献，而且对我们日益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.