雄激素通过介导HCN4的表达参与心率调节的机制研究

项目名称： 雄激素通过介导HCN4的表达参与心率调节的机制研究

项目编号： No.81470459

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈柯萍

作者单位： 中国医学科学院阜外医院

项目金额： 73万元

中文摘要： 缓慢性心律失常是临床常见的致死致残疾病之一，发病机制尚不明确。HCN4是目前公认维持基本心率的主要离子通道，其功能与表达异常是缓慢性心律失常的重要病理生理机制，也是各因素参与心率调节的最终通路。研究发现，雄激素与心率变化有关，并在一定程度上调控HCN4基因的表达，但作用与具体机制均未明确。结合国内外文献，我们提出雄激素通过介导HCN4的表达，参与基本心率的维持与调节的假设。本研究拟通过在转染人HCN4的乳鼠心肌细胞上探讨不同剂量睾酮对HCN4功能与表达的影响，并从基因分子水平阐明雄激素参与心率调节的具体机制。进一步在犬模型上验证睾酮通过上调HCN4基因进而维持与调节心率的作用。本课题将首次探讨雄激素通过介导HCN4的表达影响心率的机制，揭示雄激素对心肌起搏细胞电生理特性的影响，从新的角度阐明缓慢性心律失常的发病基础，为今后心动过缓的防治提供新思路，具有重要的理论意义和一定的应用价值。

中文关键词： 缓慢性心律失常；HCN4；心率调节；雄激素；离子通道

英文摘要： As one of the most common arrhythmias, bradycardia has a high mortality and disability rate. However, its pathogenesis hasn't been fully illustrated. HCN4 is considered to be the pacemaker ion channel maintaining basic heart rate and acts as the final common path for other factors regulating heart rate. Abnormality of the function and expression of HCN4 is a crucial physiopathologic mechanism in bradycardia. Androgen has been found to be related to change of heart rate and regulation of HCN4 expression in previous studies, but the precise influence and concrete mechanism weren't explicit. On such basis, we hypothesized that the influence of androgen on heart rate regulation is mediated by modulating HCN4 expression. Our study will be divided into two parts. The first part is designed to investigate the influence of different doses of testosterone on the function and expression of HCN4 as well as the definite mechanism at gene and molecular levels using neonatal rat myocardial cells transfected with human HCN4 genes. Furthermore, the verification of our hypothesis will be carried out by canine models in the second part. The mechanism that the influence of androgen on heart rate regulation is mediated by modulating HCN4 expression will be investigated in this study for the first time. By illuminating how androgen affects the electrophysiological characters of cardiac pacemaker cells, we will provide a new insight into the pathogenesis basis of bradycardia and a new idea for its treatment.

英文关键词： Bradycardia;HCN4;Modulation of heart rate;Androgen;Ion Channel