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
基本信息
- 批准号:10682378
- 负责人:
- 金额:$ 3.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:ActinsAdultAnimal ModelAnimalsAnti-Arrhythmia AgentsAreaArrhythmiaBindingBiochemistryCardiacCardiac Electrophysiologic TechniquesCardiac MyocytesCause of DeathCellsChronicChronic stressComplexCytoskeletal ProteinsDataDevelopmentDiseaseElectrophysiology (science)FellowshipFunctional disorderGenesGoalsHandHealthHealthcareHeartHeart DiseasesHeart failureHomeostasisHumanIntercalated discInterventionIonsKnockout MiceLifeLinkMapsMembraneMissionModelingMolecularMolecular BiologyMolecular Biology TechniquesMuscle CellsMutationOpticsOrganPathologyPathway interactionsPatientsPermeabilityPotassium ChannelPredispositionPrevalenceProteinsRattusReagentRegulationResearchRiskRoleScientistSpectrinStressTechniquesTestingTrainingTranslation InitiationUnited StatesUnited States National Institutes of HealthVariantVentricular ArrhythmiaWorkbetaIV spectrinburden of illnesscare burdencostdisabilityheart preservationhigh riskin vivoinnovationmouse modelnovelnovel therapeutic interventionpharmacologicpreservationpressurepreventresponsesudden cardiac deathvoltage
项目摘要
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)是美国的主要死亡原因,并且患病率正在增长。HF
患者因室性心律失常而发生心脏性猝死的风险较高,尽管在
了解HF的病理,目前的心律失常治疗受到疗效、成本和风险的限制。
手术并发症。尽管该领域已经确定了一系列电生理和结构变化,
在HF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TREK 1在细胞凋亡中的新作用。
调节心律失常易感性和兴奋性。我们实验室以前的工作已经发现肌动蛋白-
相关的细胞骨架蛋白β IV-血影蛋白协调TREK 1膜定位。但如何
血影蛋白调节TREK 1功能,以及TREK 1/血影蛋白复合物的破坏如何导致疾病,
仍是未知数我们实验室的初步数据表明,在没有与血影蛋白相互作用的情况下,
TREK 1的电流-电压关系和反转电位发生了变化。这表明离子的变化
渗透性,这与患者和大鼠模型的研究一致,这些研究表明TREK 1
可能由于突变或替代翻译起始而变得对Na可渗透。
基于这些初步的研究,我的建议的中心假设是,β IV-血影蛋白的损失,
对慢性应激的反应促进异常TREK 1活性,导致改变的肌细胞离子稳态,
心律失常易感性增加。我将采用光学标测,电生理学,
分子生物学技术来确定TREK 1/血影蛋白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,钙和钠处理,和蛋白质共-
定位经受压力超负荷的心脏,以评估慢性心力衰竭过程中TREK 1的失调是否
应激促进异常的离子体内平衡和电重构,这是促神经元的。最后,
将评估旨在保持正常TREK 1活性的药理学和基于基因的干预措施,
它们在慢性应激期间保持体内心脏电功能的能力。总的来说,这项研究
有可能为预防HF患者的促发性癫痫触发因素提出新的治疗方法,
最终推进国家卫生研究院的使命“增进健康,延长寿命,减少疾病和残疾”。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Cemantha M. Lane其他文献
Cemantha M. Lane的其他文献
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{{ truncateString('Cemantha M. Lane', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 3.57万 - 项目类别:
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