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

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.

项目概要 心律失常是心脏病死亡的主要原因。功能丧失的患者 锚蛋白 B (AnkB) 基因 (ANK2) 的变异表现出严重且复杂的心脏表型，包括窦性心脏病 淋巴结功能障碍、心房颤动 (AF)、心率变异性 (HRV)、传导缺陷、儿茶酚胺能 多形性室性心律失常（CPVT）和/或心源性猝死。此外，之前的研究已经 表明普通人群中常见的 ANK2 基因变异与 QTc 改变相关 室性心律失常易感性，以及大型心血管动物模型中 AnkB 水平发生改变 疾病。虽然这些研究为心律失常的常见机制和机制提供了重要的见解。 获得性疾病的形式，他们还发现了我们对控制疾病的理解中的重要差距 自主神经系统控制心率和节律。鉴于自主控制异常的重要性 在心律失常和疾病中，了解其重要的潜在分子途径至关重要 靶向关键膜受体/通道。 该 K99/R00 提案重点关注离子通道/膜蛋白的新作用和机制 人类心脏自动性的调节。此 K99/R00 提案涵盖了意想不到但直接相关的领域 心律失常生物学，每个都直接集成临床、转化和机械平台。这个提议是 基于临床和分子数据，证明 AnkB 在调节 两个 IKACh 通道亚基 G 蛋白激活的内向整流（GIRK1 和 GIRK4）调节心脏“战斗或逃跑”反应以及对胆碱能反应的心房兴奋性 刺激。我们确定了 AnkB/GIRK 的直接相互作用，并发现了携带 GIRK4 的心律失常患者 阻止交互的变体。由于房性心律失常和不适当的心率是独立的预测因素 心血管死亡率和 IKACh 失调是房性心律失常的一个主要标志，这些发现将 对先天性和后天性人类心房疾病都有影响。我们假设锚蛋白-B 在调节心房中 GIRK4/GIRK1 的分子靶向和稳定方面发挥着未被认识到的关键作用 窦房结组织，从而控制交感/副交感平衡来调节心率。我们进一步 假设锚蛋白 B 通路功能障碍是由于锚蛋白 B 表达减少或人锚蛋白 - B 功能丧失变异导致 GIRK 亚基调节丧失并改变心脏自律性。我们将 1) 确定 GIRK1/GIRK4 组装和膜靶向的分子机制； 2）确定新角色 GIRK/IKACh 和自主调节中基于 AnkB 的通路； 3) 定义AnkB/GIRK4复合物在人类中的作用 基线和疾病状态下的心房肌细胞。