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; 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重极化电流的组合很好地控制。人们认为，许多内部和外部离子电流的细胞调节和失调在许多临床相关的心律不齐中起着重要作用。实际上，现在已经很好地确定，即使是由离子通道功能障碍引起的心脏作用潜在特性的细微变化也可能导致心脏疾病被称为通道病。经典形式主义教导说，离子通道根据其个体时间和依赖电压的生物物理特性独立于彼此独立起作用。这是开发用于了解单细胞电生理行为的计算机模型的基础。然而，在布鲁加达综合征（BRS）中，钠通道突变引起的一种遗传心律不齐的形式，介导钾（ITO）和钠（INA）电流之间的功能相互作用已被认为参与了两种主要心律失常机制：复隔离障碍障碍和传导障碍障碍障碍。因此，是否有可能协调介导这两种主要电流的离子通道亚基的调节？值得注意的是，我们最近的工作是第一个支持这种挑衅性观念的研究，即去极化钠通道的表达和复极化钾通道ITO可能具有一种常见但尚未确定的调节机制。在ITO的附件亚基KCHIP2基因沉默之后，申请人发现ITO和INA的表达被废除了产生不可脱颖而出的心肌细胞。这表明可以协调介导这两种主要电流的离子通道的调节。这将代表有关离子通道表达和调节的范式转移概念。因此，我们假设KCHIP2通过多种调节机制控制去极化（INA）和复极（ITO）电流的表达。该提案的具体目的是：1。确定由KCHIP2调节的基因。 2。确定INA和ITO的调控是否涉及microRNA。 3。定义Kchip2 miRNA依赖性调节在心脏病理学中的作用。该调节的分子基础的描述对于准确理解心室去极化和复极化及其与致命性心室心律不齐相关的扰动至关重要。 KCHIP2的进一步功能解剖将为心脏功能的许多方面提供洞察力，将阐明Kchip2蛋白质家族在疾病中的作用，并可能在健康和疾病中揭示离子通道功能的新型范式。 公共卫生相关性：该项目将为离子电流的功能关联和调节提供新的批判性见解，这对于正常的去极化和心脏中的重极化至关重要。了解钠和钾电流调节的机制将有助于我们理解它们对患病状态的参与。