Cardiac Ion Channel Regulation

心脏离子通道调节

• 批准号: 7993375
• 负责人: Isabelle Deschenes
• 金额: $ 39.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-06 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993375
• 关键词: Action Potentials; Affect; Arrhythmia; Behavior; Biological Assay; Brain; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cavia; Cells; Code; Complex; Computer Simulation; Data; Development; Disease; Dissection; Educational process of instructing; Electrophysiology (science); Family member; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genetic Transcription; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Human Genome; In Vitro; Individual; Ion Channel; Ions; Knock-out; Kv channel-interacting protein 2; Lead; Link; Measures; Mediating; Messenger RNA; MicroRNAs; Modeling; Modification; Molecular; Mus; Mutation; Myocardium; Names; Pathology; Physiological; Play; Potassium; Potassium Channel; Property; Protein Family; Proteins; RNA Interference; RNA Splicing; Regulation; Role; Small RNA; Sodium; Sodium Channel; Surface; Syndrome; System; Testing; Time; Translations; Variant; Ventricular; Ventricular Arrhythmia; Work; base; calsenilin; clinically relevant; fascinate; indium arsenide; insight; loss of function; novel; overexpression; public health relevance; research study; trafficking; voltage

DESCRIPTION (provided by applicant): Cardiac excitability is finely controlled by a combination of depolarizing and repolarizing currents. Fine regulation and dysregulation of a host of inward and outward ion currents are thought to play a major role in numerous clinically relevant cardiac arrhythmias. In fact, it is now well established that even subtle alterations of the cardiac action potential properties caused by dysfunction of ion channels, may lead to cardiac disorders known as channelopathies. Classic formalism teaches that ion channels function independently of each other according to their individual time- and voltage- dependent biophysical properties. This is the basis for computer models developed to understand single cell electrophysiological behavior. However, in Brugada syndrome (BrS), a form of genetic arrhythmia caused by mutations in the sodium channel, functional interaction between channels mediating potassium (Ito) and sodium (INa) currents has been suggested to be involved in the two main arrhythmogenic mechanisms: repolarization disorder and conduction disorder hypothesis. Thus, is it possible that the regulation of ion channel subunits mediating these two major currents of the cardiac action potential is coordinated? Notably, our recent work was the first to support this provocative idea that the expression of the depolarizing sodium channel and the repolarizing potassium channel Ito may share a common, yet to be identified, regulatory mechanism. Following gene silencing of KChIP2, an accessory subunit of Ito, the applicant found that the expression of Ito and INa was abolished producing a non-excitable cardiac myocytes. This suggested that the regulation of ion channel mediating these two major currents could be coordinated. This would represent a paradigm-shifting concept regarding ion channels expression and regulation. Therefore, we hypothesize that KChIP2 controls the expression of depolarizing (INa) and repolarizing (Ito) currents through multiple regulatory mechanisms. The specific aims of this proposal are to: 1. Identify genes modulated by KChIP2. 2. Determine if the regulation of INa and Ito involves microRNA(s). 3. Define the role of KChIP2 miRNA-dependent regulation in cardiac pathology. The delineation of the molecular basis of this regulation is essential for an accurate understanding of cardiac ventricular depolarization and repolarization and its derangements that are associated with lethal ventricular arrhythmias. Further functional dissection of KChIP2 will provide insight into numerous aspects of cardiac function will illuminate the role of the KChIP2 family of proteins in disease and likely unveil novel paradigms for ion channel function in health and disease. PUBLIC HEALTH RELEVANCE: This project will provide new critical insights into the functional association and regulation of ionic currents that are essential to normal depolarization and repolarization in the heart. Understanding the mechanisms of regulation of sodium and potassium currents will contribute to our understanding of their involvement in diseased states.

描述（由申请人提供）：心脏兴奋性由去极化和再极化电流的组合精细控制。向内和向外离子电流的精细调节和失调被认为在许多临床相关的心律失常中起主要作用。事实上，现在已经确定，即使是由离子通道功能障碍引起的心脏动作电位特性的细微改变，也可能导致称为通道病变的心脏疾病。经典的形式主义告诉我们，离子通道根据它们各自依赖于时间和电压的生物物理特性，彼此独立地起作用。这是为理解单细胞电生理行为而开发的计算机模型的基础。然而，在Brugada综合征（BrS）中，一种由钠通道突变引起的遗传性心律失常，介导钾（Ito）和钠（INa）电流的通道之间的功能相互作用被认为涉及两种主要的心律失常机制：复极化障碍和传导障碍假说。因此，离子通道亚基介导心脏动作电位的这两大电流的调节是否可能是协调的？值得注意的是，我们最近的工作首次支持了这一具有挑衅性的观点，即去极化钠通道和复极化钾通道Ito的表达可能具有共同的，但尚未确定的调节机制。在沉默Ito的附属亚基KChIP2基因后，申请人发现Ito和INa的表达被消除，产生不可兴奋的心肌细胞。这表明离子通道调节这两大电流是可以协调的。这将代表一个关于离子通道表达和调控的范式转换概念。因此，我们假设KChIP2通过多种调节机制控制去极化（INa）和再极化（Ito）电流的表达。本建议的具体目的是：1。鉴定受KChIP2调控的基因。2. 确定INa和Ito的调控是否涉及microRNA。3. 明确KChIP2 mirna依赖性调控在心脏病理中的作用。描述这种调控的分子基础对于准确理解与致命性室性心律失常相关的心室去极化和复极化及其紊乱至关重要。对KChIP2的进一步功能解剖将为心脏功能的许多方面提供见解，将阐明KChIP2蛋白家族在疾病中的作用，并可能揭示离子通道在健康和疾病中的功能的新范式。