Role of TREK-1 in modulating cardiac excitability and arrhythmia

TREK-1 在调节心脏兴奋性和心律失常中的作用

• 批准号: 10576871
• 负责人: Thomas Jeffrey Hund
• 金额: $ 42.67万
• 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: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576871
• 关键词: Action Potentials; Adjuvant Therapy; Adrenergic Agents; Anti-Arrhythmia Agents; Arrhythmia; Automobile Driving; Biochemistry; Biomechanics; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cells; Cessation of life; Chronic; Chronic stress; Clinical Trials; Computer Models; Computer Simulation; Cytoskeleton; Data; Defect; Development; Electrophysiology (science); Face; Fibrosis; Functional disorder; Genes; Genetic; Goals; Heart; Homeostasis; Human; Image; In Vitro; Inherited; Intervention; Ion Channel; Ions; Knockout Mice; Link; Mechanics; Membrane; Modeling; Molecular; Mus; Muscle Cells; Organ; Pathway interactions; Patients; Permeability; Polyunsaturated Fatty Acids; Population; Potassium Channel; Precision therapeutics; Predisposition; Publishing; RNA Splicing; Reagent; Regulation; Regulatory Pathway; Reporting; Risk; Role; Signal Pathway; Signal Transduction; Spectrin; Stimulus; Stress; Testing; Therapeutic; Time; Tissues; Variant; cost; druggable target; experimental study; heart preservation; in vivo; mouse model; multimodality; new therapeutic target; next generation; novel; novel strategies; novel therapeutics; patient tolerability; personalized approach; pharmacologic; potassium channel protein TREK-1; preservation; pressure; prevent; response; sensor

Project Summary/Abstract Cardiac electrical rhythm disturbances (arrhythmias) contribute to over 500,000 deaths each year in patients with cardiovascular disease (CVD). Despite considerable advances in defining the specific cell- and organ-level remodeling changes associated with CVD, the precise mechanisms driving increased susceptibility to arrhythmia remain to be defined. At the same time, existing anti-arrhythmic therapies are limited by efficacy, low patient tolerance, risk of procedural complications, and/or cost. In particular, the development of new anti- arrhythmic drugs has been hampered by high profile failed clinical trials involving compounds that target major cardiac ion channels, leading to a shift away from the pursuit of population wide, “blockbuster” therapies and towards more precise, patient-specific approaches. Essential for this effort will be the development of novel adjuvant therapies that tune cardiac excitability without introducing large scale perturbations in the cardiac action potential. Here, we explore the two-pore K+ channel TREK-1 as an ideal, although understudied, candidate for next generation “precision” therapeutics based on: 1) endogenous expression in cardiomyocytes across species, including mouse and human; 2) multiple regulatory modes for tuning of channel activity; and 3) recent emergence as a highly druggable target. Importantly, TREK-1 is sensitive to a wide range of environmental stimuli, including mechanical membrane deformation, β-adrenergic stimulation, polyunsaturated fatty acids, and intracellular pH. While defects in TREK-1 expression/function have been identified in inherited and acquired models of arrhythmia and in human patients, little is known about the mechanism linking neurohumoral/biomechanical stress stimuli to TREK-1 dysfunction, or the specific role for TREK-1 in modulating arrhythmia risk. This proposal is further motivated by mounting data that TREK-1 displays noncanonical activity beyond its primary function as a repolarizing K+ current. At the same time, our unexpected preliminary data indicate that TREK-1 ion selectivity depends on the integrity of the spectrin-based cytoskeleton in cardiac myocytes. Together, these findings provide a potential link between stress-induced changes in the cytoskeleton, TREK-1 dysfunction and downstream remodeling relevant to arrhythmia in the setting of CVD. Our long-term goal is to define new regulatory pathways underlying adverse remodeling and arrhythmia in the setting of CVD, and to identify novel anti-arrhythmia strategies in CVD patients. The central hypothesis of this proposal is that TREK-1 functions as a multimodal stress sensor in heart, as well as therapeutic “lever” that may be tuned to modulate cardiac excitability through association with the spectin-based cytoskeleton. Further, we expect that chronic biomechanical/neurohumoral stress induces noncanonical TREK-1 activity thereby promoting dysregulation of ion homeostasis in cardiac myocytes and increased risk for arrhythmia.

项目摘要/摘要 心脏电性节律疾病（心律不齐）每年造成超过500,000人死亡 心血管疾病（CVD）的患者。尽管在定义特定细胞和 器官级的重塑变化与CVD相关，驱动的精确机制提高了易感性 心律不齐仍有待定义。同时，现有的抗心律失常疗法受到轻松的限制， 患者容忍度低，程序并发症和/或成本。特别是，新的反 - 心律不齐的药物受到涉及主要针对主要的化合物的临床试验的较高的临床试验的阻碍 心脏离子渠道，导致人们从对人口广泛的“大片”疗法和 采取更精确的患者特定方法。这项工作至关重要的是发展小说 辅助疗法可调节心脏兴奋性，而无需在心脏动作中引入大规模扰动 潜在的。在这里，我们探索了两孔K+频道Trek-1作为理想，尽管被理解为候选人 基于：1）跨物种的心肌细胞中的内源性表达的下一代“精度”疗法， 包括老鼠和人； 2）多种调节模式用于调整通道活动； 3）最近出现 作为高度吸毒的目标。重要的是，TREK-1对广泛的环境刺激敏感，包括 机械膜变形，β-肾上腺素能刺激，多不饱和脂肪酸和细胞内pH。 虽然在心律不齐的遗传和获取模型中已经确定了Trek-1表达/功能中的缺陷 在人类患者中，关于联系神经肿瘤/生物力学应力刺激的机制知之甚少 TREK-1功能障碍，或Trek-1在调节心律失常风险中的特定作用。该提议进一步 通过安装数据的激励，trek-1显示出非规范活动的主要功能，作为一个 重新极化K+电流。同时，我们意外的初步数据表明Trek-1离子选择性 取决于心肌细胞中基于光谱的细胞骨架的完整性。这些发现一起提供了 应力诱导的细胞骨架，Trek-1功能障碍和下游变化之间的潜在联系 在CVD的情况下，与心律不齐相关的重塑。我们的长期目标是定义新的监管途径 在CVD的情况下，基础不良重塑和心律不齐，并鉴定新的抗心律失常 CVD患者的策略。该提议的中心假设是Trek-1充当多模式 心脏中的应力传感器以及可以调节以调节心脏兴奋性的治疗“杠杆” 与基于光谱的细胞骨架相关。此外，我们期望慢性生物力学/神经瘤 压力诱导非规范的TREK-1活动，从而促进心脏内部离子稳态失调 心肌细胞和心律不齐的风险增加。