Electrophysiological robustness in developing and adult heart.

描述（由申请人提供）： 总结 正常的心脏电功能依赖于心肌和传导组织中离子通道的适当表达。通道表达模式的不受调节的改变可导致心律失常，心律失常是世界范围内死亡的主要原因之一。在心脏发育过程中，不同细胞中离子通道表达的正确模式是如何确定的，以及哪些因素调节最终的通道表达水平还知之甚少。更好地理解这些过程将提供洞察系统如何在面对各种各样的干扰时建立稳定的电气功能。本提案的一个长期目标是了解心脏电功能发展过程中关键时期的功能。在这些时期，电功能的至少某些方面的成熟似乎受到反馈调节，可能是通过感知钙流入细胞。我们已经开发了一种小鼠模型的心脏特异性诱导基因敲除的离子通道亚基KChIP2，使我们能够研究的性质和时间的一个关键时期。我们的初步研究结果表明，KChIP2基因敲除在成年动物产生致命的心脏电功能的缺陷。与此形成鲜明对比的是，如果在出生后早期诱导KChIP2基因敲除，尽管KChIP2和瞬时外向电流对小鼠心肌细胞的电特性很重要，但大多数小鼠仍能存活。本申请的第一个目标是使用电生理学和分子技术的组合来鉴定在成人中KCHIP 2基因敲除后导致致死性的机制。第二个目标是使用诱导敲除系统来表征出生后发育的关键时期，在此期间，动物可以有效地补偿KChIP2亚基的损失。

DESCRIPTION (provided by applicant): Summary Normal cardiac electrical function relies on appropriate expression of ion channels in the myocardium and conducting tissues. Unregulated alterations in the pattern of channel expression can result in cardiac arrhythmias, which are one of the leading causes of mortality worldwide. How the correct patterns of ion channel expression are determined in different cells during cardiac development and what factors regulate final channel expression levels are poorly understood. A better understanding of these processes will provide insight into how the system can establish stable electrical function in the face of a wide variety of disturbances. One long term goal of this proposal is to understand the function of critical periods during the development of cardiac electrical function. These are periods when maturation of at least some aspects of electrical function appears to be subject to feedback regulation, possibly by sensing calcium fluxes into the cell. We have developed a mouse model of cardiac-specific inducible gene knockout of the ion channel subunit KChIP2 that allows us to study the nature and timing of one critical period. Our preliminary results show that KChIP2 gene knockout in adult animals produces a lethal deficit in cardiac electrical function. In marked contrast, if KChIP2 gene knockout is induced during the early postnatal period, the majority of mice survive, despite the importance of KChIP2 and the transient outward current for the electrical properties of mouse cardiac myocytes. The first goal of this application is to identify the mechanisms that lead to lethality following KCHIP2 gene knockout in the adult, using a combination of electrophysiological and molecular techniques. The second goal is to use the inducible knockout system to characterize the critical period in postnatal development during which the animals can effectively compensate for the loss of the KChIP2 subunit.