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: 10157170
• 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/10157170
• 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; In Vitro; Inherited; Intervention; Ion Channel; Ions; Knockout Mice; Link; Mechanics; Membrane; Modeling; Mus; Muscle Cells; Organ; Pathway interactions; Patients; Permeability; Pharmacology; 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; base; cost; druggable target; experimental study; heart preservation; in vivo; molecular imaging; mouse model; multimodality; new therapeutic target; next generation; novel; novel strategies; novel therapeutics; patient tolerability; personalized approach; 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 心电节律紊乱(心律失常)每年导致50多万人死亡。 心血管疾病(CVD)患者。尽管在定义特定细胞方面取得了相当大的进步--以及 与心血管疾病相关的器官水平重塑变化--导致易感性增加的确切机制 对心律失常的认识尚不明确。与此同时，现有的抗心律失常疗法受到疗效的限制， 患者耐受性低、出现手术并发症的风险和/或费用。特别是新型防弹技术的发展 心律失常药物一直受到高调失败的临床试验的阻碍，这些试验涉及针对主要 心脏离子通道，导致从追求全人群范围的“重磅炸弹”疗法和 转向更精确的、针对患者的方法。这一努力的关键是小说的发展 调整心脏兴奋性而不会在心脏活动中引入大规模扰动的辅助治疗 潜力。在这里，我们探索两孔K+通道Trek-1作为理想的，尽管研究不足，候选 下一代“精确”疗法基于：1)跨物种心肌细胞的内源性表达， 包括老鼠和人类；2)多种调节模式，调节通道活动；3)最近出现的 作为一个高度可下药的目标。重要的是，Trek-1对广泛的环境刺激很敏感，包括 机械性膜变形、β肾上腺素能刺激、多不饱和脂肪酸和细胞内pH。 而在遗传性和获得性心律失常模型中已发现Trek-1表达/功能缺陷 在人类患者中，对神经体液/生物力学应激刺激之间的联系机制知之甚少。 Trek-1功能障碍，或Trek-1在调节心律失常风险中的特定作用。这项建议是进一步的 受到越来越多的数据的推动，Trek-1显示了超出其主要功能的非规范活动 使K+电流重新极化。与此同时，我们出人意料的初步数据表明，Trek-1离子选择性 这取决于心肌细胞中以血影蛋白为基础的细胞骨架的完整性。总而言之，这些发现提供了 应激诱导的细胞骨架改变、Trek-1功能障碍和下游之间的潜在联系 心血管疾病背景下与心律失常相关的重构。我们的长期目标是定义新的监管途径 心血管疾病背景下潜在的不良重构和心律失常，并确定新的抗心律失常药物 脑血管病患者的治疗策略。这一提议的中心假设是Trek-1作为多模式 心脏中的压力感应器，以及可以调节以调节心脏兴奋性的治疗性“杠杆” 与基于spectin的细胞骨架相关联。此外，我们预计慢性生物力学/神经体液 应激诱导非典型性Trek-1活性，从而促进心脏离子稳态失调 心肌细胞和增加心律失常的风险。