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

窦房结（SAN）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SAN起搏来实现的，窦房结功能障碍是人体植入起搏器的主要原因。一个主要的去极化电流在SAN细胞，如果，已被提出作为主要的起搏器在生理条件下，但这样的功能的直接证据仍然缺失，因为功能丧失的小鼠突变体缺乏如果在胚胎发育阶段死亡。If由cAMP结合HCN通道介导。为了克服HCN敲除动物胚胎致死性的局限性，我们将使用具有功能性（显性负突变）和可逆性（Tet-Off系统）失活的HCN起搏通道的条件转基因小鼠系。这些小鼠线，我们计划研究的生理和病理生理作用的HCN通道的心脏起搏，自主控制，传导，收缩性，并适应增加的工作量在成人心脏。

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.