Electrophysiological robustness in developing and adult heart.

描述(由申请人提供)： 摘要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控制的变化可能导致心律失常，这是全球死亡的主要原因之一。在心脏发育过程中，离子通道表达的正确模式是如何在不同的细胞中确定的，以及哪些因素调节最终的通道表达水平，目前还知之甚少。更好地了解这些过程将有助于深入了解系统如何在面对各种干扰时建立稳定的电气功能。这项建议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作用。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，可能是通过感知钙离子流入细胞。我们已经建立了一种心脏特异性诱导基因敲除离子通道亚单位KChIP2的小鼠模型，使我们能够研究一个关键期的性质和时间。我们的初步结果表明，在成年动物中，KChIP2基因敲除会导致心脏电功能的致命缺陷。相比之下，如果KChIP2基因敲除是在出生后早期诱导的，大多数小鼠都能存活下来，尽管KChIP2和瞬时外向电流对小鼠心肌细胞的电特性很重要。这项应用的第一个目标是利用电生理学和分子技术相结合的方法，识别导致成人KChIP2基因敲除后致死的机制。第二个目标是使用可诱导的基因敲除系统来描述动物在出生后发育的关键期，在此期间动物可以有效地补偿KChIP2亚单位的丢失。

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.