Investigation of cardiac ion channel modulation in mouse models

小鼠模型心脏离子通道调制的研究

• 批准号: 13327368
• 负责人: Professor Dr. Olaf Pongs
• 金额: --
• 依托单位: Fachrichtung Physiologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2005
• 资助国家: 德国
• 起止时间: 2004-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/13327368?language=en
• 关键词: Investigation; cardiac; ion; channel; modulation

Human KCNQ1 and HERG genes encode ¿-subunits of voltage-gated potassium-channels that mediate IKs and, respectively, IKr-. The currents are major determinants of ventricular action potential repolarization. Mutations in KCNQ1 and HERG are associated with an abnormally prolonged electrocardiographic QT interval, the long QT syndrome (LQTS). Physical and emotional stress often precipitates in LQTS patients life threatening episodes of ventricular tachycardias with a high risk of sudden death. The molecular basis of the trigger which connects mutant IKr or IKs channel expression to episodic occurrence of ventricular arrhythmia, is not clear. We hypothesize that a ventricular arrhythmia may eventually occur because mutant IKr or IKs channels do not properly respond to adrenergic signaling pathways in ventricular myocytes. Specifically, we plan to test this hypothesis in transgenic mouse lines that express LQT mutants which produce in heterologous expression systems functional channels, but are insensitive to adrenergic signaling pathways. Furthermore, we want to investigate the importance of multiprotein signaling complexes for spatiotemporal regulation of cardiac IKs and/or IKr channel activity. The results are expected to further our understanding of dynamic regulation of IKs and/or IKr channel activity by adrenergic signaling pathways and its pathophysiological consequences.

人类KCNQ1和HERG基因编码电压门控钾通道的？亚基，分别介导IKS和IKR-。电流是心室动作电位复极的主要决定因素。KCNQ1和HERG基因突变与心电图QT间期异常延长有关，即长QT综合征(LQTS)。LQTS患者经常出现危及生命的室性心动过速发作，并有较高的猝死风险。突变的IKR或IKS通道表达与室性心律失常的间歇性发生之间的联系的分子基础尚不清楚。我们推测，室性心律失常的最终发生可能是因为突变的IKR或IKS通道不能对心室肌细胞中的肾上腺素能信号通路做出正确的反应。具体地说，我们计划在表达LQT突变体的转基因小鼠品系中测试这一假设，这些突变体在异源表达系统中产生功能通道，但对肾上腺素能信号通路不敏感。此外，我们想要研究多蛋白信号复合体对于心脏iKs和/或iKr通道活动的时空调节的重要性。这些结果有望加深我们对肾上腺素能信号通路对IKs和/或IkR通道活性的动态调节及其病理生理后果的理解。