Administrative Supplement -Circadian Clock Regulation of Myocardial Ion Channel Expression and Function

摘要 这一多样性补充建议旨在1)定义基因组和转录组机制，通过这些机制 心肌细胞时钟调节有助于心脏兴奋性的离子通道，并2)扰乱 心肌细胞时钟将昼夜节律基因表达的变化与电生理和 心肌细胞的收缩特性。结果将解决我们在理解上的重大差距 心肌生物钟如何调节关键的心脏离子通道的表达以及如何 心脏时钟功能异常导致心律失常和收缩易损性。 调节昼夜节律的机制，即分子钟，几乎存在于人体所有类型的细胞中。 分子钟的一个关键功能是将一天中的时间与大规模转录程序联系起来 来维持细胞的动态平衡。Delisle和Esser实验室使用了一种可诱导的心肌细胞特异性 小鼠模型敲除核心时钟基因BMal1(ICSΔBMal1)。他们的研究表明，颠覆 的心肌钟足以降低心肌K+和Na+通道基因的表达，扰乱 目前的水平，扰乱心脏的兴奋性，并增加心律失常的易感性。这些研究建立了一个 心肌细胞时钟的关键作用，独立于中枢时钟，调节 影响正常兴奋性所需离子平衡的不同离子通道基因家族。一 这个项目的目标是在我们的小鼠模型中利用大规模的基因组和转录组方法 用于定义心房和心房肌中时间基因表达的昼夜节律依赖时钟控制的系统 脑室组织。此外，这一补充旨在了解分子的破坏是如何 心肌细胞时钟改变了心肌细胞的机械功能。布莱尔博士将产生 关于心脏异常生物钟如何导致收缩功能障碍的新的初步数据， 父母奖的目标是了解改变的生物钟是如何增加的 心律失常易损性。 这一提议旨在检验以下假设：1)心房和心室的分子时钟 心肌细胞是指导日常染色质可及性和转录输出所必需的，包括 关键离子通道和离子通道调控基因的表达。2)心肌细胞时钟被打乱 会导致心脏离子通道表达和电流失衡，导致兴奋性改变， 心律失常易感性增加，收缩功能障碍。

Abstract This diversity supplement proposal aims to 1) define the genomic and transcriptomic mechanisms by which the cardiomyocyte clock regulates ion channels that contribute to cardiac excitability and 2) disrupt the cardiomyocyte clock to link changes in circadian-ordered gene expression with electrophysiological and contractile properties of cardiomyocytes. The outcomes will address significant gaps in our understanding of how the myocardial circadian clock regulates the expression of critical cardiac ion channels and how abnormal cardiac clock function contributes to arrhythmia and contractile vulnerability. The mechanism regulating circadian timing, the molecular clock, exists in virtually all cell types in the body. A critical function of the molecular clock is to link the time of day with a large-scale transcriptional program to support cellular homeostasis. The Delisle and Esser labs have used an inducible cardiomyocyte-specific mouse model to knock out the core clock gene, Bmal1 (iCSΔBmal1). Their studies showed that disruption of the myocardial clock is sufficient to decrease ventricular K+ and Na+ channel gene expression, disrupt current levels, disrupt cardiac excitability, and increase arrhythmia susceptibility. These studies establish a critical role for the cardiomyocyte clock, independent of the central clock, in regulating the expression of different families of ion channel genes that impact the ionic balance needed for normal excitability. One goal of this project is to utilize large-scale genomic and transcriptomic approaches with our mouse model system to define the circadian clock-dependent control of temporal gene expression in both atrial and ventricular tissues. Additionally, this supplement aims to understand how disruption to the molecular cardiomyocyte clock alters the mechanical function of ventricular cardiomyocytes. Dr. Blair will generate new preliminary data on how an abnormal circadian clock in the heart contributes to contractile dysfunction, an extension of the parent award's goal of understanding how an altered circadian clock increases arrhythmia vulnerability. This proposal aims to test the following hypotheses: 1) The molecular clocks in both atrial and ventricular cardiomyocytes are necessary to direct daily chromatin accessibility and transcriptional output, including expression of key ion channel and ion channel regulatory genes. 2) Disruption of the cardiomyocyte clock will result in an imbalance in cardiac ion channel expression and currents, leading to altered excitability, increased arrhythmia vulnerability, and contractile dysfunction.