Transcriptional Regulation of Ion Channels in Heart Failure and Arrhythmias

心力衰竭和心律失常中离子通道的转录调节

• 批准号: 10084059
• 负责人: Isabelle Deschenes
• 金额: $ 59.96万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084059
• 关键词: Transcriptional; Regulation; Ion; Channels; Heart

 DESCRIPTION (provided by applicant): Cardiac arrhythmias are a leading cause of morbidity and mortality within developed nations. Often, these arrhythmias are associated with acquired heart diseases, notably cardiac heart failure (HF), where the dysregulation of a host of ion transporters and channels is observed. Particularly, a critical imbalance of both depolarizing INa and repolarizing Ito is observed. Our previous work was the first to support the nascent idea that expression of INa and Ito may share common, yet to be identified regulatory mechanisms involving KChIP2, an accessory subunit of Ito. KChIP2 silencing produced simultaneous mRNA degradation and potential translational block of multiple genes at the source of INa and Ito, suggesting a mechanism of microRNA activity, which led to significant loss of Ito and INa. These results suggested KChIP2 may have additional nuclear functions as a transcription factor to regulate other critical cardiac currents. Indeed, a member of the KChIP family found in neuronal tissues, KChIP3, also known as DREAM, is localized to the nucleus where it acts as a Ca2+-regulated transcriptional repressor. Given KChIP2 shares a high degree of sequence homology with DREAM and that it has been found in the nucleus, one can hypothesize that KChIP2 is capable of similar nuclear roles in cardiac settings. Therefore, we hypothesize that KChIP2 controls expression of depolarizing INa and repolarizing Ito through a novel posttranscriptional mechanism involving microRNAs. Indeed, our preliminary data show evidence demonstrating KChIP2 transcriptionally regulates a family of miRNAs known as miR-34s which we demonstrate targets genes involved in generating both INa and Ito. However the significance of this pathway under pathologic conditions is unknown and is the central focus of this proposal. We hypothesize that KChIP2 loss in the diseased heart (hypertrophy and/or HF) is responsible for dysfunction of cardiac excitability at the level of gene expression. Given that KChIP2 is significantly repressed in HF, our specific aims are to: 1. Define the role of KChIP2 miRNA-dependent regulation in cardiac pathology. 2. Evaluate the influence of restored KChIP2 expression on arrhythmia susceptibility and HF progression. 3. Evaluate the influence of miRNA blockade by antagomirs on arrhythmia susceptibility and heart failure progression. To test these aims rat and guinea pig heart failure models produced by transverse aortic constriction (TAC) and the canine pacing-induced HF model will be used. Delivery of either KChIP2 through viral vectors or miR-34 blockade by injection of miRNA antagomirs will be used to assess influence over INa and Ito expression as well as overall arrhythmia susceptibility and HF progression. The delineation of the molecular basis of KChIP2 regulation is essential for an accurate understanding of cardiac depolarization and repolarization and its implications with lethal ventricular arrhythmias.

 描述（由适用提供）：心律不齐是发达国家发病率和死亡率的主要原因。通常，这些心律不齐与获得的心脏病有关，尤其是心脏衰竭（HF），其中观察到许多离子转运蛋白和通道的失调。特别是，观察到分推了INA和重生ITO的严重失衡。我们以前的工作是第一个支持新生想法的想法，即INA和ITO的表达可能共同，但可以识别出涉及ITO的附件亚基Kchip2的调节机制。 KCHIP2沉默产生了INA和ITO来源的多个基因的同时mRNA降解和潜在的翻译块，这表明了MicroRNA活性的机制，从而导致ITO和INA的显着丧失。这些结果表明，KCHIP2可能具有额外的核功能作为调节其他关键心脏电流的转录因子。的确，在神经元组织中发现的Kchip家族的成员Kchip3（也称为Dream）位于核局部，在该核能中充当Ca2+调节的转录复制品。鉴于KCHIP2与Dream具有高度的序列同源性，并且在核中发现了它，因此可以假设Kchip2能够在心脏环境中具有相似的核角色。因此，我们假设KCHIP2通过一种新的涉及microRNA的新的文字后机制来控制脱离INA的表达并重新降低ITO。确实，我们的初步数据显示了证据，证明KCHIP2在转录上调节了一个称为miR-34的miRNA家族，我们证明了与产生INA和ITO的基因有关。但是，在病理条件下，该途径的重要性尚不清楚，并且是该提案的中心重点。我们假设在基因表达水平下，disseed骨心脏（肥大和/或HF）中的KCHIP2丧失导致心脏兴奋性功能障碍。鉴于Kchip2在HF中显着反映，我们的具体目的是：1。定义Kchip2 miRNA依赖性调节在心脏病理学中的作用。 2。评估恢复的Kchip2表达对心律不齐敏感性和HF进展的影响。 3。评估Antagomirs对心律失常敏感性和心力衰竭进展的miRNA封锁的影响。为了测试这些目标，将使用横向主动脉收缩（TAC）产生的大鼠和豚鼠心力衰竭模型，并将使用犬只起搏诱导的HF模型。通过注入miRNA Antagomirs通过病毒载体或miR-34阻断进行Kchip2，将用于评估对INA和ITO表达的影响以及总体心律不齐的敏感性和HF进展。 KCHIP2调节的分子基础的描述对于准确理解心脏沉积和重极化及其与致命的心室心律不齐的意义至关重要。

项目成果

Multilayer control of cardiac electrophysiology by microRNAs.

• DOI: 10.1016/j.yjmcc.2022.02.007
• 发表时间: 2022-05
• 期刊: JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
• 影响因子: 5
• 作者: Yang, Dandan;Desche, Isabelle;Fu, Ji-Dong
• 通讯作者: Fu, Ji-Dong

Inhibition of CREB-CBP Signaling Improves Fibroblast Plasticity for Direct Cardiac Reprogramming.

• DOI: 10.3390/cells10071572
• 发表时间: 2021-06-22
• 期刊: Cells
• 影响因子: 6
• 作者: Bektik E;Sun Y;Dennis AT;Sakon P;Yang D;Deschênes I;Fu JD
• 通讯作者: Fu JD

KChIP2 regulates the cardiac Ca2+ transient and myocyte contractility by targeting ryanodine receptor activity.

• DOI: 10.1371/journal.pone.0175221
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Nassal DM;Wan X;Liu H;Laurita KR;Deschênes I
• 通讯作者: Deschênes I

S-phase Synchronization Facilitates the Early Progression of Induced-Cardiomyocyte Reprogramming through Enhanced Cell-Cycle Exit.

• DOI: 10.3390/ijms19051364
• 发表时间: 2018-05-04
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Bektik E;Dennis A;Pawlowski G;Zhou C;Maleski D;Takahashi S;Laurita KR;Deschênes I;Fu JD
• 通讯作者: Fu JD