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

行政补充-心肌离子通道表达和功能的昼夜节律时钟调节

• 批准号: 10800220
• 负责人: Brian P Delisle
• 金额: $ 22.96万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10800220
• 关键词: ARNTL gene; Administrative Supplement; Arrhythmia; Award; Biological Models; Cardiac; Cardiac Myocytes; Chromatin; Circadian Dysregulation; Data; Disease; Electrophysiology (science); Family; Functional disorder; Gene Expression; Gene Order; Genes; Genetic Transcription; Genomics; Goals; Heart; Heart Abnormalities; Heart Atrium; Homeostasis; Ion Channel; Knock-out; Link; Mechanics; Molecular; Molecular Target; Myocardial; Outcome; Outcome Study; Output; Parents; Predisposition; Property; Regulation; Regulator Genes; Risk; Role; Testing; Time; Tissues; Ventricular; Ventricular Function; cell type; circadian; circadian pacemaker; ionic balance; molecular clock; mouse model; patient population; programs; transcriptomics; translational framework; virtual

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.

摘要 该多样性补充提案旨在1）定义基因组和转录组机制， 心肌细胞时钟调节离子通道，离子通道有助于心脏兴奋性和2）破坏 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。这些成果将解决我们认识上的重大差距 心肌生物钟如何调节关键心脏离子通道的表达， 异常的心脏时钟功能导致心律失常和收缩脆弱性。 调节昼夜节律的机制，即分子钟，几乎存在于体内所有类型的细胞中。 分子钟的一个关键功能是将一天中的时间与大规模的转录程序联系起来 来维持细胞内稳态Delisle和Esser实验室使用了一种诱导型心肌细胞特异性 敲除核心时钟基因Bmal 1（iCS Δ Bmal 1）的小鼠模型。他们的研究表明， 心肌时钟的变化足以降低心室钾离子和钠离子通道基因表达， 电流水平，破坏心脏兴奋性，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，独立于中央时钟，在调节表达 影响正常兴奋性所需的离子平衡的离子通道基因的不同家族。一 这个项目的目标是利用大规模的基因组和转录组的方法与我们的小鼠模型 系统来定义心房和心房肌中时间基因表达的昼夜节律钟依赖性控制， 心室组织此外，这种补充旨在了解如何破坏分子 心肌细胞时钟改变心室心肌细胞的机械功能。布莱尔博士会 关于心脏异常生物钟如何导致收缩功能障碍的新初步数据， 父母奖的目标是了解改变的生物钟如何增加 心律失常脆弱性 本研究旨在验证以下假设：1）心房和心室的分子钟 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节基因的表达。2)心肌细胞时钟的中断 将导致心脏离子通道表达和电流的不平衡，导致兴奋性改变， 增加心律不齐的脆弱性和收缩功能障碍。

项目成果

Circadian clocks regulate cardiac arrhythmia susceptibility, repolarization, and ion channels.

• DOI: 10.1016/j.coph.2020.09.015
• 发表时间: 2021-04
• 期刊: Current opinion in pharmacology
• 影响因子: 4
• 作者: Delisle BP;Stumpf JL;Wayland JL;Johnson SR;Ono M;Hall D;Burgess DE;Schroder EA
• 通讯作者: Schroder EA

Cardiovascular research and the arrival of circadian medicine.

心血管研究和昼夜节律医学的到来。

• DOI: 10.1080/07420528.2022.2151862
• 发表时间: 2023
• 期刊: Chronobiology international
• 影响因子: 2.8
• 作者: Martino,TamiA;Delisle,BrianP
• 通讯作者: Delisle,BrianP

Time Restricted Feeding to the Light Cycle Dissociates Canonical Circadian Clocks and Physiological Rhythms in Heart Rate.

• DOI: 10.3389/fphar.2022.910195
• 发表时间: 2022
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Schroder, Elizabeth A.;Delisle, Brian P.
• 通讯作者: Delisle, Brian P.

The role of the cardiomyocyte circadian clocks in ion channel regulation and cardiac electrophysiology.

• DOI: 10.1113/jp282402
• 发表时间: 2022-05
• 期刊: JOURNAL OF PHYSIOLOGY-LONDON
• 影响因子: 5.5
• 作者: Schroder, Elizabeth A.;Ono, Makoto;Johnson, Sidney R.;Rozmus, Ezekiel R.;Burgess, Don E.;Esser, Karyn A.;Delisle, Brian P.
• 通讯作者: Delisle, Brian P.

Caution: merging ion channel traffic ahead.

注意：合并前面的离子通道流量。

• DOI: 10.1113/jp284497
• 发表时间: 2023
• 期刊: The Journal of physiology
• 作者: Burgess,DonE;Delisle,BrianP
• 通讯作者: Delisle,BrianP