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

窦房结是心脏的生理起搏器，主要负责自主心跳的产生。心率控制是通过自主神经系统控制窦房结起搏来实现的，而窦房结功能障碍是人类植入起搏器的主要原因。在生理条件下，SAN细胞中的一种主要的去极化电流IF被认为是主要的起搏器，但这种功能的直接证据仍然缺乏，因为缺乏功能缺失的小鼠突变体IF在胚胎发育阶段死亡。IF是由cAMP结合的HCN通道介导的。为了克服HCN基因敲除动物胚胎致死的局限性，我们将使用具有功能性(显性负突变)和可逆性(Tet-Off系统)灭活的HCN起搏通道的条件转基因小鼠系。利用这些小鼠系，我们计划研究HCN通道在成人心脏的心脏起搏、自主神经控制、传导、收缩和适应增加的负荷中的生理和病理生理学作用。

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.