Analysis of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function in adult heart using conditional transgenic mouse models

使用条件转基因小鼠模型分析成年心脏中超极化激活的环核苷酸门控（HCN）通道功能

• 批准号: 13327398
• 负责人: Professor Dr. Dirk Isbrandt
• 金额: --
• 依托单位: Institut für Molekulare und Verhaltensneurowissenschaften
• 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/13327398?language=en
• 关键词: Analysis; hyperpolarization; activated; cyclic; nucleotide

The sinoatrial node (SAN) is the physiological pacemaker of the heart and is predominantly responsible for autonomous heart beat generation. Heart rate control is achieved through control of SAN pacemaking by the autonomic nervous system, and sinus node dysfunction is a major cause for pacemaker implantation in humans. A major depolarizing current in SAN cells, If, has been proposed to act as the primary pacemaker under physiological conditions, but direct evidence for such a function is still missing, since loss-of-function mouse mutants lacking If die during embryonic stages of development. If is mediated by cAMP-binding HCN channels. To overcome the limitation of embryonic lethality in HCN knockout animals, we will use conditional transgenic mouse lines with functionally (dominant negative mutations) and reversibly (Tet-Off system) inactivated HCN pacemaker channels. With these mouse lines we plan to study the physiological and pathophysiological roles of HCN channels in cardiac pacemaking, autonomic control, conduction, contractility, and adaptation to increased workload in the adult heart.

Sinotrial节点（SAN）是心脏的生理起搏器，主要负责自主性心跳的一代。心率控制是通过自主神经系统控制San Pacemaking实现的，而窦性淋巴结功能障碍是人类起搏器植入的主要原因。 SAN细胞中的主要去极化电流（如果已被提议）在生理条件下充当主要的起搏器，但是仍然缺少这种功能的直接证据，因为如果在发育的胚胎阶段死亡，则缺乏功能丧失的小鼠突变体。如果是由营地结合HCN通道介导的。为了克服HCN基因敲除动物中胚胎致死性的局限性，我们将使用有条件的转基因小鼠线，具有功能（主要的负突变）和可逆的（Tet-Off System）灭活的HCN HCN Pacemaker通道。使用这些小鼠线，我们计划研究HCN通道在心脏起搏，自主控制，传导，收缩性和适应成人心脏工作量增加的生理和病理生理作用。