Defining new pathways for cardiac automaticity

定义心脏自动性的新途径

• 批准号: 10434964
• 负责人: Mona El Refaey
• 金额: $ 24.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434964
• 关键词: ANK2 gene; Animal Model; Ankyrins; Area; Arrhythmia; Atrial Fibrillation; Autonomic nervous system; Biological; Biology; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular system; Carrier Proteins; Cell membrane; Cells; Cessation of life; Clinical; Complex; Data; Defect; Disease; Electrophysiology (science); Equilibrium; Functional disorder; GIRK1 subunit, G protein-coupled inwardly-rectifying potassium channel; GIRK4 subunit, G protein-coupled inwardly-rectifying potassium channel; GTP-Binding Proteins; General Population; Genes; Goals; Heart Atrium; Heart Diseases; Heart Rate; Human; Ion Channel; Mechanical Stress; Membrane; Membrane Proteins; Mentors; Modeling; Molecular; Molecular Target; Muscle Cells; Pathway interactions; Patients; Phase; Phenotype; Phosphorylation; Play; Predisposition; Property; Proteins; Regulation; Reporting; Role; Signaling Protein; Sinoatrial Node; Sinus; Stimulus; Testing; Therapeutic; Tissues; Variant; Ventricular; Ventricular Arrhythmia; Work; base; cholinergic; fighting; genetic variant; heart rate variability; heart rhythm; human disease; insight; loss of function; mortality; novel; prevent; receptor; response; sudden cardiac death; trafficking; ANK2 gene; Animal Model; Ankyrins; Area; Arrhythmia; Atrial Fibrillation; Autonomic nervous system; Biological; Biology; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular system; Carrier Proteins; Cell membrane; Cells; Cessation of life; Clinical; Complex; Data; Defect; Disease; Electrophysiology (science); Equilibrium; Functional disorder; GIRK1 subunit, G protein-coupled inwardly-rectifying potassium channel; GIRK4 subunit, G protein-coupled inwardly-rectifying potassium channel; GTP-Binding Proteins; General Population; Genes; Goals; Heart Atrium; Heart Diseases; Heart Rate; Human; Ion Channel; Mechanical Stress; Membrane; Membrane Proteins; Mentors; Modeling; Molecular; Molecular Target; Muscle Cells; Pathway interactions; Patients; Phase; Phenotype; Phosphorylation; Play; Predisposition; Property; Proteins; Regulation; Reporting; Role; Signaling Protein; Sinoatrial Node; Sinus; Stimulus; Testing; Therapeutic; Tissues; Variant; Ventricular; Ventricular Arrhythmia; Work; base; cholinergic; fighting; genetic variant; heart rate variability; heart rhythm; human disease; insight; loss of function; mortality; novel; prevent; receptor; response; sudden cardiac death; trafficking

Project Summary Cardiac arrhythmias are a major cause of mortality in heart disease. Patients harboring loss-of-function variants in the ankyrin-B (AnkB) gene (ANK2) display severe and complex cardiac phenotypes, including sinus node dysfunction, atrial fibrillation (AF), heart rate variability (HRV), conduction defects, catecholaminergic polymorphic ventricular arrhythmia (CPVT), and/or sudden cardiac death. Moreover, previous studies have shown that common ANK2 gene variants in the general population are associated with QTc alterations and ventricular arrhythmia susceptibility, and that AnkB levels are altered in large animal models of cardiovascular disease. While these studies have provided important insight into arrhythmia mechanisms in common and acquired forms of disease, they have also identified important gaps in our understanding regarding control of heart rate and rhythm by the autonomic nervous system. Given the importance of abnormal autonomic control in cardiac arrhythmia and disease, it is essential to understand the underlying molecular pathways important for targeting of key membrane receptors/channels. This K99/R00 proposal focuses on new roles and mechanisms underlying ion channel/membrane protein regulation in human cardiac automaticity. This K99/R00 proposal covers unexpected, but directly related areas of arrhythmia biology, each directly integrating clinical, translational, and mechanistic platforms. This proposal is based on clinical and molecular data demonstrating a key and unexpected role of AnkB in regulating the assembly and targeting of the two IKACh channel subunits G-protein-activated inwardly rectifying (GIRK1 and GIRK4) that regulate cardiac `fight or flight' responses as well as atrial excitability in response to cholinergic stimuli. We identified direct AnkB/GIRK interactions and uncovered patients with arrhythmias harboring GIRK4 variants that block the interaction. As atrial arrhythmias and inappropriate heart rate are independent predictors of cardiovascular mortality and IKACh dysregulation is a major hallmark of atrial arrhythmias, these findings will have impact on both congenital and acquired forms of human atrial disease. We hypothesize that ankyrin-B plays a key unrecognized role regulating the molecular targeting and stabilization of GIRK4/GIRK1 in atria and sinoatrial node tissue, thus controlling sympathetic/parasympathetic balance to tune the heart rate. We further hypothesize that dysfunction in the ankyrin-B pathway due to reduced ankyrin-B expression or human ankyrin- B loss-of-function variants results in loss of GIRK subunit regulation and altered cardiac automaticity. We will 1) Identify molecular mechanisms for GIRK1/GIRK4 assembly and membrane targeting; 2) Identify novel roles for AnkB-based pathways in GIRK/IKACh & autonomic regulation; 3) Define roles of AnkB/GIRK4 complex in human atrial myocytes at baseline & in disease.

项目摘要 心律不齐是心脏病死亡率的主要原因。具有功能丧失的患者 Ankyrin-B（ANKB）基因（ANK2）中的变体显示严重而复杂的心脏表型，包括窦 节点功能障碍，房颤（AF），心率变异性（HRV），传导缺陷，儿茶酚胺能 多态性心律失常（CPVT）和/或心脏猝死。而且，以前的研究有 表明一般人群中常见的ANK2基因变异与QTC改变有关 心律不齐的敏感性，并且在大型心血管模型中ANKB水平发生了变化 疾病。尽管这些研究为心律失常机制提供了重要的见解， 获得的疾病形式，他们还确定了我们对控制的理解的重要差距 自主神经系统的心率和节奏。鉴于异常自主控制的重要性 在心律不齐和疾病中，必须了解对基础分子途径至关重要 关键膜受体/通道的靶向。 该K99/R00提案重点介绍了离子通道/膜蛋白的新作用和机制 人类心脏自动化的调节。该K99/R00提案涵盖了意外但直接相关的领域 心律失常生物学，每种都直接整合临床，翻译和机械平台。该提议是 基于临床和分子数据，证明了ANKB在调节的关键和意外作用 两个IKACH通道亚基G蛋白激活的组装和靶向内部整流（Girk1和 GIRK4）调节心脏“战斗或飞行”反应以及对胆碱能的心房兴奋性 刺激。我们确定了直接的ANKB/GIRK相互作用，并发现携带Girk4的心律不齐患者 阻止相互作用的变体。由于心律不齐和不适当的心率是独立的预测因子 心血管死亡率和IKACH失调是心律不齐的主要标志，这些发现将会 对先天性和获得形式的人心房疾病产生影响。我们假设Ankyrin-B 扮演着关键的角色，调节了girk4/girk1在心房中的分子靶向和稳定 窦淋巴结组织，因此控制交感/副交感神经平衡以调整心率。我们进一步 假设由于arnkyrin-b的表达降低或人类arnkyrin- b功能丧失的变体导致GIRK亚基调节的损失和心脏自动化改变。我们将1） 确定GIRK1/GIRK4组件和膜靶向的分子机制； 2）确定新的角色 Girk/Ikach和自主法规中的基于ANKB的途径； 3）定义ANKB/GIRK4复合物在人类中的作用 基线和疾病的心肌细胞。