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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要心脏电节律紊乱（心律失常）每年导致超过 500,000 人死亡尽管在定义特定细胞和心血管疾病（CVD）方面取得了相当大的进展。与CVD相关的器官水平重塑变化，驱动易感性增加的精确机制同时，现有的抗心律失常疗法仍受到疗效的限制。患者耐受性低、手术并发症的风险和/或成本特别是新抗肿瘤药物的开发。心律失常药物一直受到引人注目的失败临床试验的阻碍，这些临床试验涉及针对主要目标的化合物心脏离子通道，导致人们不再追求人群范围内的“重磅炸弹”疗法这项工作的关键是开发新颖的、针对患者的更精确的方法。调节心脏兴奋性而不会对心脏活动造成大规模扰动的辅助疗法在这里，我们探索了双孔 K+ 通道 TREK-1 作为一种理想的候选者，尽管尚未得到充分研究。下一代“精准”疗法基于：1）跨物种心肌细胞的内源表达，包括小鼠和人类；2）调节通道活动的多种调节模式；以及3）最近出现的重要的是，TREK-1 对多种环境刺激敏感，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 值。虽然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，人们对神经体液/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具体作用，进一步说明了这一点。受越来越多数据的推动，TREK-1 显示了超出其主要功能的非规范活动同时，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，这些发现共同提供了这一结果。应激引起的细胞骨架变化、TREK-1 功能障碍和下游之间的潜在联系我们的长期目标是定义新的监管途径。 CVD 背景下潜在的不良重塑和心律失常，并新鉴定抗心律失常药物该提案的中心假设是 TREK-1 作为多模式药物发挥作用。心脏中的压力传感器，以及可以通过调整来调节心脏兴奋性的治疗“杠杆” 此外，我们预计慢性生物力学/神经体液。压力会诱导非典型 TREK-1 活性，从而促进心脏离子稳态失调肌细胞并增加心律失常的风险。