钠钾ATP酶作为细胞膜"感知分子"对胆固醇代谢调节机制研究

项目名称： 钠钾ATP酶作为细胞膜"感知分子"对胆固醇代谢调节机制研究

项目编号： No.81200637

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 李欣

作者单位： 华中科技大学

项目金额： 23万元

中文摘要： 钠钾ATP酶是细胞维持跨膜离子梯度的关键结构，除经典的离子泵功能，它还具有信号传导等非离子泵功能；约50%的钠钾ATP酶及胆固醇分布在膜穴内。基于我们前期研究成果：钠钾ATP酶可调控胆固醇合成、转运及分布；本项目进一步推测，钠钾ATP酶是细胞膜胆固醇感知分子，通过"胆固醇-钠钾ATP酶-Src/ERK-SREBP2-胆固醇"信号通路调节胆固醇代谢。本课题拟通过FRET技术，研究钠钾ATP酶与胆固醇作用方式，其次分析两者相互作用是否激活Src/ERK信号通路，最后证明通过激活Src/ERK从而激活SREBP2信号通路调节胆固醇合成及分布。胆固醇是人体组织不可缺少的重要物质，研究发现许多胆固醇代谢障碍性疾病，如动脉粥样硬化、高血压等都伴随钠钾ATP酶表达改变。本研究结果将阐明钠钾ATP酶调节胆固醇代谢的作用机制，为以钠钾ATP酶做为靶蛋白研制出针对动脉粥样硬化等疾病的治疗提供新方案和理论依据。

中文关键词： 钠/钾ATP酶；胆固醇；相互作用；分子机制；

英文摘要： The Na+/K+-ATPase, also known as "Sodium Pump", is a ubiquitous transmembrane enzyme that transports Na+ and K+ arcoss the plasma membrane by hydrolyzing ATP. Recently it has been demonstrated that cardiotonic steroids, such as ouabain binds to Na+/K+-ATPase generating a large number of secondary messengers. Binding of ouabain to the Na+/K+-ATPase/Src complex changes their interaction, results in the activation of Src/ERK cascades.Caveolae are flask-shaped invaginations of plasma membrane and are enriched in cholesterol, glycosphingolipids and sphingomyelin.The non-pumping pool of Na+/K+-ATPase and more than 50% of total cellular cholesterol mainly resides in caveolae. We have reported that Na+/K+-ATPase regulates cholesterol synthesis, distribution and trafficking. This project is to further clarify the molecular mechanism and link it to cholesterol-associated syndromes. Due to a large number of Na+/K+-ATPase colocalizes with cholesterol in caveolae and its activity is affected by cholesterol, it is possible that the two interact with each other. When we search Na+/K+-ATPaseα1 subunit for a potential cholesterol binding consensus (-L/V-(X) 1-5-Y-(X) 1-5-R/K-), we find two potential binding sites, one around the first transmembrane domain，the other at the last transmembrane domain. Interestingly, they are highly

英文关键词： Na+/K+-ATPase；cholesterol；relationship；molecular mechanism；