Involvement of TWIK-related K+ channel in cardiac disease and arrhythmia

TWIK相关K通道与心脏病和心律失常的关系

• 批准号: 10387461
• 负责人: Cemantha M. Lane
• 金额: $ 3.48万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387461
• 关键词: Actins; Adult; Animal Model; Animals; Area; Arrhythmia; Binding; Biochemistry; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Cause of Death; Cells; Chronic; Chronic stress; Complex; Cytoskeletal Proteins; Data; Development; Disease; Electrophysiology (science); Fellowship; Functional disorder; Genes; Goals; Hand; Health; Healthcare; Heart; Heart Diseases; Heart failure; Homeostasis; Human; Intercalated disc; Intervention; Ions; Knockout Mice; Life; Link; Maps; Membrane; Mission; Modeling; Molecular; Molecular Biology; Molecular Biology Techniques; Muscle Cells; Mutation; Optics; Organ; Pathology; Pathway interactions; Patients; Permeability; Pharmacology; Potassium Channel; Predisposition; Prevalence; Proteins; Rattus; Reagent; Regulation; Research; Risk; Role; Scientist; Spectrin; Stress; Techniques; Testing; Training; Translation Initiation; United States; United States National Institutes of Health; Variant; Ventricular Arrhythmia; Work; base; betaIV spectrin; burden of illness; cost; disability; heart preservation; high risk; in vivo; innovation; mouse model; novel; novel therapeutic intervention; preservation; pressure; prevent; response; sudden cardiac death; voltage

Project Summary Heart failure (HF) is a leading cause of death in the United States and is growing in prevalence. HF patients are at higher risk for sudden cardiac death from ventricular arrhythmias, and despite major strides in understanding the pathology of HF, current arrhythmia treatments are limited by efficacy, cost, and risk of procedural complications. Although the field has identified a host of electrophysiological and structural changes in HF, the precise link between chronic stress and arrhythmia remains to be defined. Recent studies have identified a novel role for the two-pore domain background K channel TREK1 in regulating arrhythmia susceptibility and excitability. Previous work from our lab has found that the actin- associated cytoskeletal protein βIV-spectrin orchestrates TREK1 membrane localization. However, how spectrin modulates TREK1 function, and how disruption of a TREK1/spectrin complex contributes to disease, is still largely unknown. Preliminary data from our lab suggests that in the absence of interaction with spectrin, TREK1 current-voltage relationships and reversal potentials are shifted. This suggests a change in ion permeability, which would be consistent with studies in patients and rat models that have shown that TREK1 may become permeable to Na as a result of mutations or alternative translation initiation. Based on these preliminary studies, the central hypothesis of my proposal is that loss of βIV-spectrin in response to chronic stress promotes aberrant TREK1 activity leading to altered myocyte ion homeostasis and increased arrhythmia susceptibility. I will employ a combination of optical mapping, electrophysiology, and molecular biology techniques to determine the role of the TREK1/spectrin complex in the regulation of cardiac excitability. Additionally, I will evaluate cardiac electrophysiology, Ca and Na handling, and protein co- localization of hearts subjected to pressure overload to assess whether dysregulation of TREK1 during chronic stress promotes aberrant ion homeostasis and electrical remodeling that is pro-arrhythmic. Finally, pharmacological and gene-based interventions aimed at preserving normal TREK1 activity will be evaluated for their ability to preserve cardiac electrical function in vivo during chronic stress. Overall, this study has the potential to suggest novel therapeutic approaches for preventing proarrhythmic triggers in HF patients, ultimately advancing the NIH’s mission “to enhance health, lengthen life, and reduce illness and disability.”

项目摘要 心力衰竭（HF）是美国死亡的主要原因，并且在患病率上正在增长。 HF 患者患心室心律不齐的心脏猝死的风险较高，而多斯蒂特（Dospite 了解HF的病理，当前心律不齐治疗受效率，成本和风险的限制 程序并发症。尽管该领域已经确定了许多电生理和结构变化 在HF中，慢性应激与心律不齐之间的精确联系尚待定义。 最近的研究已经确定了两孔域背景K通道Trek1的新作用 调节心律不齐的敏感性和兴奋性。我们实验室的先前工作发现肌动蛋白 相关的细胞骨架蛋白β-spectrin策划Trek1膜定位。但是，如何 Spectrin调节TREK1功能，以及Trek1/Spectrin复合物的破坏对疾病的影响如何 仍然是未知的。我们实验室的初步数据表明，在没有与谱的相互作用的情况下 TREK1电流电压关系和逆转电势被移动。这表明离子发生了变化 渗透性与患者和大鼠模型的研究相一致，这些研究表明Trek1 由于突变或替代翻译起始，可能会渗透到NA。 基于这些初步研究，我提出的提议的核心假设是，β-spectrin在 对慢性压力的反应会促进异常TREK1活性，从而导致肌细胞稳态变化和 心律不齐的敏感性增加。我将采用光学映射，电生理学和 分子生物学技术来确定Trek1/Spectrin复合物在心脏调节中的作用 兴奋性。此外，我将评估心脏电生理学，CA和NA处理以及蛋白质共同处理 受到压力超负荷的心脏的定位，以评估慢性期间Trek1的失调 应力促进异常心律失常的异常离子稳态和电重塑。最后， 将评估旨在保留正常TREK1活性的基于药理和基因的干预措施 他们在慢性应激期间保持体内心脏电气功能的能力。总体而言，这项研究具有 有可能提出新型治疗方法来预防HF患者的心律失常触发因素， 最终促进NIH的使命“增强健康，延长生命并减少疾病和残疾”。