分拣连接蛋白调控心脏电生理稳态的机制研究

项目名称： 分拣连接蛋白调控心脏电生理稳态的机制研究

项目编号： No.31271214

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 陈义汉

作者单位： 同济大学

项目金额： 90万元

中文摘要： 离子通道在心肌细胞中的精准空间分布是维持心脏电生理稳态的前提。特异结合到膜肌醇磷脂的一种蛋白结构域（Phox homolog，PX）是执行蛋白定向运输功能的重要结构基础之一。分拣连接蛋白（sorting nexin，SNX）是包含PX结构域的最主要分子家族。我们发现，SNXs在人类心肌细胞中存在着差异性分布，其中SNX17主要定位在心肌细胞内小体系统。我们还发现，上调心肌细胞内SNX17可以导致多种离子通道和交换体（例如L型钙通道和钠氢交换体等）的表达水平的下降。提示SNXs具有多向性调节心肌细胞离子通道和交换体稳态的潜能。我们拟在前期研究基础之上，采用分子生物学、电生理学、和斑马鱼模式生物学等实验技术，进一步确立特定SNX分子在心肌细胞中的表达与分布特征和对心脏电活动稳态的影响，进而探索其对心脏电活动稳态的调控机制。我们的研究将为心脏电生理稳态调控提供新的视角和潜在靶标。

中文关键词： 分选连接蛋白；心脏电生理；离子通道；动作电位；复极化

英文摘要： The precise spatial arrangements of the ion channels in the cardiac myocyte is the foundation to maintain the electrophysiological homeostasis of the heart . The Phox homolog (PX) protein domain, which specifically binds to membrane inositol phospholipids, is the important structural base for the implementation of the directional transport of proteins within cells. Sorting connexins (SNXs) are the major family members of the molecules that contain the PX domain. We found that SNXs had differential subcellular distribution in human cardiac myocytes. Among them, sorting nexin 17 mainly located in the endosomal system of cardiac myocytes. We also found that up-regulation of SNX-17 in cardiac myocytes leaded to down-regulation of a variety of membrane ion channel proteins and transporters such as type L calcium channel and sodium hydrogen exchanger, which indicated that SNXs have the potential of multidirectional regulating cardiac myocyte membrane ion channel and transporter stability. Based on the results we have already gained, we propose to utilize various molecular biology, electrophysiology techniques and model organism zebra fish to explore the expression and subcellular localization of the SNXs molecules in the heart and then to systematically examine the mechanisms of SNXs regulating the cardiac electrophys

英文关键词： Sorting nexins；Cardiac electrophysiology；Ion channels；Action potentials；Cardiac repolarization