心肌细胞脂肪酸代谢产生的能量与信号广泛地调控心脏生物电活动相关的离子通道、转运体和缝隙连接通道蛋白等。脂蛋白受体广泛地介导脂肪酸代谢及其相关的胞内信号转导。作为一大类重要的脂蛋白受体，低密度脂蛋白受体相关蛋白（LRPs）包含十多个家族成员，它们兼具细胞脂质代谢与胞内信号调控的功能。我们的初步研究发现，LRP6的心肌特异性敲除不但导致心肌细胞间缝隙连接通道蛋白的胞内运输缺陷，还引起心肌细胞膜L-型钙通道电流的明显降低；此外还诱发严重的心律失常和心源性猝死。我们假设：LRPs在心脏电生理稳态维持和心律失常的发生中潜在着重要作用。本项目拟探索心肌细胞膜LRPs在心肌细胞电活动稳态维持和心脏节律紊乱发生中的作用；揭示心肌细胞膜LRPs调控心肌细胞生物电活动的电生理学机制；阐释LRPs调控心肌细胞电生理稳态的分子通路和细胞生物学机制，最终为临床心律失常的防治提供新的基础理论和干预策略。

The bioenergy and signaling derived from fatty metabolism widely modulate the functioning of sarcolemmal ion channels, transporters and gap junction proteins. Lipoprotein receptors serve as critical modulators for cellular fatty metabolism and the related signaling transduction; however, their roles in the cardiac bioelectricity remain unknown. The low-density lipoprotein receptor related proteins (LRPs) are the subfamily of lipoprotein receptors, composing of more than ten members and modulating cellular fatty metabolism and signaling. Our preliminary study identified that conditional cardiac-specific knockout of LRP6 impaired the intracellular trafficking of connexins, the core gap junction protein, and reduced the currents of L-type calcium channel, leading to the increased susceptibility to lethal cardiac arrhythmogenesis. Thus, we propose that LRPs may play an important role in the regulation of cardiac electrophysiological homeostasis and arrhythmogenesis. The present proposal aims to establish the role of sarcolemmal LRPs in cardiac electrophysiology and arrhythmogenesis, uncover the electrophysiological mechanisms underlying the LRPs-mediated regulation of cardiac bioelectricity and elucidate the potential molecular pathways and cell biological mechanisms, which may eventually provide new insights into the preventive and therapeutic strategy for cardiac arrhythmias.