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

项目摘要 心力衰竭(HF)在美国是主要的死亡原因，而且患病率正在上升。高频 患者因室性心律失常而猝死的风险更高，尽管在... 了解心力衰竭的病理，目前的心律失常治疗受到疗效、成本和风险的限制。 程序上的复杂性。尽管该领域已经发现了一系列电生理和结构变化 在心力衰竭患者中，慢性应激和心律失常之间的确切联系仍有待确定。 最近的研究已经确定了双孔结构域背景K通道TREK1在 调节心律失常易感性和兴奋性。我们实验室之前的研究发现，肌动蛋白- 相关细胞骨架蛋白βIV-SPECTIN协调TREK1膜定位。然而，如何 血影蛋白调节TREK1的功能，以及TREK1/血影蛋白复合体的破坏如何导致疾病， 在很大程度上仍不为人所知。我们实验室的初步数据表明，在没有与幽灵蛋白相互作用的情况下， TREK1的电流-电压关系和反转电位被移位。这表明离子发生了变化。 通透性，这与对患者和大鼠模型的研究表明TREK1是一致的 可能由于突变或替代翻译启动而变得对Na具有渗透性。 基于这些初步研究，我的建议的中心假设是βIV-SPECTIN的丢失 对慢性应激的反应促进TREK1活性异常，导致心肌细胞离子动态平衡改变 心律失常易感性增加。我将综合运用光学测绘、电生理学和 用分子生物学技术确定TREK1/Spectrin复合体在心脏调节中的作用 兴奋性。此外，我将评估心脏电生理学，钙和钠的处理，以及蛋白质协同 通过对压力超负荷心脏的定位来评估TREK1在慢性心肌病过程中的调节异常 应激促进异常的离子动态平衡和促心律失常的电重构。最后， 旨在保持正常TREK1活性的药理学和基于基因的干预措施将被评估 它们在慢性应激期间在体内保存心脏电功能的能力。总体而言，这项研究具有 提出预防心力衰竭患者心律失常诱发因素的新治疗方法的潜力， 最终推进美国国立卫生研究院“增进健康、延长寿命、减少疾病和残疾”的使命。

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.”