IP3R1在成年小鼠心室传导系统中的作用及机制研究

室性心律失常是心脏性猝死的主要原因，浦肯野细胞电活动异常对其发生起着关键作用，但具体机制尚不清楚。IP3R在心肌细胞中表达并参与心律失常病理过程的调控，其在浦肯野细胞中的表达量远大于工作心肌细胞。预实验发现，浦肯野细胞中IP3R1敲除影响胞内钙信号、延长小鼠心室电信号的传导，在心脏缺血时更易诱导房室阻滞。假设：IP3R1介导的钙信号参与浦肯野细胞电活动及细胞间通讯过程的调控，对心室电信号的传导以及心脏节律的维持起着重要的作用；其功能改变引起心室电活动的异常，可能参与病理条件下心律失常的调节。本项目拟通过建立浦肯野细胞特异性敲除IP3R1小鼠，研究IP3R1钙信号对浦肯野细胞的电活动及心室传导功能的调控及作用机制；并探讨在心肌缺血、心脏衰竭等病理情况下，浦肯野细胞IP3R1对心室电活动和心脏功能的影响。研究结果对明确室性心律失常的组织学起源、深入理解其机制和提高治疗效果有重要的意义。

Ventricular arrhythmias is the leading cause of sudden cardiac death, for which the electric imbalance of purkinje cells in the conduction system provides substrates. However, the underlying mechanism for purkinje cell arrhythmogenic activites keeps poorly understood. Inositol 1,4,5-trisphosphate receptors (IP3Rs) expressed in cardiac myocyte is an important participator of cardiac arrhythmias. Previously, it was reported that the expression of IP3Rs (with the main isoform IP3R1) in purkinje cells is much higher than in working myocytes. Our preliminary experiment revealed that knockout of IP3R1 in purkinje cells slowed down the ventricular conduction in physiology, and induced atrioventricular block in the langendorff-perfused heart upon ischemia. Thus, we hypothesize that the calcium release via IP3R1 in purkinje cell can modulate both the cellular action potential and the intercellular communications, which are very important for the ventricular conduction and cardiac rhythm, and the abnormal change on it can be arrhythmogenic. In the present study, we aim to explore the functional role of the purkinje IP3R1 in the ventricular conduction system in physiology and in diseases, including heart failure and myocardial ischemia, by using a mice model with the specific knockout of purkinje IP3R1. The result will be of great significance in clarifying the histological origin of ventricular arrhythmia, understanding its mechanism and improving the therapeutic effect.