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.

项目总结/摘要 心脏电节律紊乱（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展， 与CVD相关的器官水平重塑变化，驱动易感性增加的确切机制 心律不齐仍有待确定。与此同时，现有的抗疟疾疗法受到疗效的限制， 患者耐受性低、手术并发症风险和/或成本。特别是，新的反- 抗抑郁药物受到了高调失败的临床试验的阻碍，这些试验涉及靶向主要药物的化合物。 心脏离子通道，导致从追求人群范围的转变，“重磅炸弹”疗法， 更精确的针对患者的方法这一努力的关键将是小说的发展 调节心脏兴奋性而不引起心脏活动大规模扰动的辅助疗法 潜力在这里，我们探索了双孔K+通道TREK-1作为一个理想的，虽然研究不足，候选人， 下一代“精确”疗法基于：1）跨物种的心肌细胞中的内源性表达， 包括小鼠和人类; 2）用于调节通道活性的多种调节模式;以及3）最近出现的 作为一个高度可药物化的目标。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TREK-1表达/功能的缺陷已在遗传性和获得性心律失常模型中鉴定， 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。该提案进一步 在大量数据的推动下，TREK-1显示出非典型的活动，超出了它作为一个 复极化钾电流。同时，我们意想不到的初步数据表明，TREK-1离子选择性 取决于心肌细胞中基于血影蛋白的细胞骨架的完整性。这些发现提供了 应激诱导的细胞骨架变化、TREK-1功能障碍和下游细胞因子之间的潜在联系 在CVD的情况下与心律失常相关的重构。我们的长期目标是确定新的监管途径 CVD背景下潜在的不良重塑和心律失常，并确定新的抗心律失常药物 CVD患者的治疗策略。该建议的中心假设是TREK-1作为多通道 心脏中应力传感器以及治疗“杠杆”，其可以被调节以通过 与基于spectin的细胞骨架的关联。此外，我们预计慢性生物力学/神经体液 应激诱导非典型TREK-1活性从而促进心脏中离子稳态失调 增加心律失常的风险。