Targeting the parasympathetic regulation of the heart to treat arrhythmias

针对心脏的副交感神经调节来治疗心律失常

• 批准号: 9395432
• 负责人: Allison Diane Anderson
• 金额: $ 3.95万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2020-08-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395432
• 关键词: Ablation; Acetylcholine; Address; Adult; Adverse effects; Affect; Agonist; Arrhythmia; Atrial Fibrillation; Autonomic nervous system; Binding; Cardiac; Cardiac Myocytes; Cardiac Output; Cells; Characteristics; Complex; Custom; Data; Development; Disease; Electrocardiogram; Electrophysiology (science); Equilibrium; Exhibits; Family; G-Protein-Coupled Receptors; G-substrate; GIRK1 subunit, G protein-coupled inwardly-rectifying potassium channel; GIRK4 subunit, G protein-coupled inwardly-rectifying potassium channel; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genes; Genetic; Goals; Heart; Heart Atrium; Heart Diseases; Heart Rate; Human; Individual; Inherited; Ion Channel; Knockout Mice; Knowledge; Life; Light; Link; Long QT Syndrome; Mediating; Medical; Modeling; Molecular; Molecular Target; Mus; Muscarinic Acetylcholine Receptor; Muscarinic M2 Receptor; Muscle Cells; Myocardial Infarction; National Heart, Lung, and Blood Institute; Neurons; Nodal; Pathogenesis; Patients; Periodicity; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Physiological; Physiology; Play; Potassium Channel; Preparation; Receptor Activation; Regulation; Research; Role; Sick Sinus Syndrome; Signal Pathway; Stroke; System; Testing; Therapeutic; Tissues; United States; Ventricular; Ventricular Arrhythmia; Work; heart rhythm; high throughput screening; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; loss of function mutation; mouse model; novel; patch clamp; pre-clinical; small molecule; tool

PROJECT SUMMARY Dysregulation of autonomic control of the heart can provoke arrhythmias, predisposing individuals to potentially life-threatening medical problems such as myocardial infarction and stroke. Many of the medications currently available for treating arrhythmias exhibit limited efficacy and/or the potential for long-term pro-arrhythmic side effects. Accordingly, it is important to gain a more comprehensive understanding of the molecular mechanisms underlying cardiac rhythmicity, so that new and safer approaches for the treatment of arrhythmias can be developed. A long-term goal of our research is to better understand the mechanisms underlying the parasympathetic regulation of the heart and to investigate the therapeutic potential of manipulating relevant signaling pathways for the treatment of rhythm disorders. To this end, we and others have shown that a signaling pathway consisting of the M2 muscarinic receptor (M2R) and IKACh, a G protein-gated K channel + formed by GIRK1 and GIRK4 subunits, mediates much of the parasympathetic influence on heart rate and atrial physiology. While recent evidence suggests that the parasympathetic system also regulates ventricular physiology, the molecular mechanisms underlying this influence are less clear. One goal of this project is to delineate the mechanisms and relevance of the parasympathetic influence on ventricular physiology (AIM 1), testing the working hypothesis that this influence is mediated by an M2R-IKACh signaling pathway in ventricular myocytes. I will test this hypothesis using a unique array of constitutive and tissue-specific knockout mice, together with whole-cell patch-clamp electrophysiology and in vivo electrocardiogram (ECG) approaches. A second goal of this project is to begin exploring the therapeutic potential of IKACh modulators in the context of cardiac rhythm disorders (AIM 2). While numerous studies support the contention that IKACh agonists and antagonists could be used to treat certain types of arrhythmias, including atrial fibrillation, sick sinus syndrome, atrio-ventricular block, and one hereditary type of long QT syndrome (LQTS13), attempts to test this prospect have been impeded by the lack of direct-acting and selective IKACh modulators. Recent high-throughput screening efforts have led to the development of a novel family of GIRK channel agonists and antagonists. Using whole-cell electrophysiological approaches, I will evaluate the selectivity, potency, and efficacy profiles of these compounds. Those exhibiting superior pharmacodynamic characteristics, including selectivity for IKACh relative to neuronal GIRK channels, will be further evaluated in the isolated heart preparation, exploiting established genetic and pharmacologic arrhythmia models. Successful completion of the proposed project will shed new light on the mechanisms and relevance of parasympathetic regulation of the heart, and will yield critical preclinical insights required to assess the potential efficacy associated with manipulation of a key parasympathetic effector (IKACh) in the context of cardiac rhythm disorders.

项目概要 心脏自主控制失调会引发心律失常，使个体容易出现潜在的心律失常。 威胁生命的医疗问题，例如心肌梗塞和中风。目前很多药物 可用于治疗心律失常的药物表现出有限的功效和/或长期促心律失常的潜力 影响。因此，更全面地了解分子机制非常重要 潜在的心律失常，以便可以开发新的、更安全的心律失常治疗方法 发达。我们研究的长期目标是更好地了解潜在的机制 心脏的副交感神经调节并研究操纵相关的治疗潜力 用于治疗节律紊乱的信号通路。为此，我们和其他人已经证明， 信号通路由 M2 毒蕈碱受体 (M2R) 和 IKACh（G 蛋白门控 K 通道）组成 + 由 GIRK1 和 GIRK4 亚基形成，介导副交感神经对心率和心率的大部分影响 心房生理学。虽然最近的证据表明副交感神经系统也调节心室 从生理学角度来看，这种影响背后的分子机制尚不清楚。该项目的目标之一是 描述副交感神经对心室生理学影响的机制和相关性（AIM 1）， 测试工作假设，即这种影响是由心室中的 M2R-IKACh 信号通路介导的 肌细胞。我将使用一系列独特的组成型和组织特异性敲除小鼠来测试这个假设， 以及全细胞膜片钳电生理学和体内心电图（ECG）方法。一个 该项目的第二个目标是开始探索 IKACh 调节剂在以下情况下的治疗潜力： 心律失常（AIM 2）。虽然大量研究支持 IKACh 激动剂和 拮抗剂可用于治疗某些类型的心律失常，包括心房颤动、病态窦房结综合征、 房室传导阻滞和一种遗传性长 QT 综合征 (LQTS13) 试图检验这一前景 由于缺乏直接作用和选择性 IKACh 调节剂而受到阻碍。近期高通量 筛选工作导致了 GIRK 通道激动剂和拮抗剂新型家族的开发。 使用全细胞电生理学方法，我将评估选择性、效力和功效概况 这些化合物。表现出优异的药效学特征，包括对 IKACh 的选择性 相对于神经元 GIRK 通道，将在离体心脏制备中进一步评估，利用 建立了遗传和药理学心律失常模型。拟议项目的成功完成将 对心脏副交感神经调节的机制和相关性有了新的认识，并将产生 评估与关键操作相关的潜在功效所需的关键临床前见解 心律失常情况下的副交感神经效应器（IKACh）。