KCNJ2-Induced Arrhythmia Mechanisms in CPVT and Heart Failure.
KCNJ2 诱导 CPVT 和心力衰竭的心律失常机制。
基本信息
- 批准号:9975894
- 负责人:
- 金额:$ 38.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:ANK2 geneAddressAdrenergic AgentsAffinityAnkyrinsArrhythmiaBiophysical ProcessBiophysicsCALM1 geneCalciumCalmodulinCalsequestrinCardiacCatecholaminergic Polymorphic Ventricular TachycardiaCause of DeathCell modelChronicClinicalClosure by clampCyclic AMP-Dependent Protein KinasesElectrophysiology (science)Evidence based treatmentExhibitsFunctional disorderGenerationsGenesGeneticGoalsHeartHeart DiseasesHeart VentricleHeart failureHomeostasisHumanImageInterruptionIon ChannelKnock-inKnock-in MouseLeadLinkMass Spectrum AnalysisMediatingMembraneMembrane PotentialsMethodsModelingMuscle CellsMutationOpticsOrganOutcomes ResearchPatientsPharmaceutical PreparationsPhasePhenocopyPhenotypePhosphorylationPhosphorylation SitePore ProteinsPredispositionPreventionResolutionRestRyanodine Receptor Calcium Release ChannelShort QT syndromeStressSyndromeSystolic heart failureTechniquesTestingTransgenic MiceTriad Acrylic ResinUnited StatesVentricularVentricular ArrhythmiaVentricular Tachycardiaadrenergic stressbiophysical propertiesclinical phenotypedensityexperimental groupgenetic signatureimprovedin vivoinnovationinorganic phosphateinsightloss of functionmolecular dynamicsmouse modelmutantoptimal treatmentsperiodic paralysispreventresponsesudden cardiac deathtriadinvoltage
项目摘要
Arrhythmic sudden cardiac death (SCD) is a leading cause of death in the United States and can be caused by
ionic current abnormalities occurring in genetic arrhythmia syndromes or acquired heart disease such as heart
failure. This project focuses on the impact of cardiac inward rectifier current (IK1) on -adrenergic-dependent
genetic and acquired ventricular arrhythmias. IK1 maintains resting membrane potential, contributes to phase 3
repolarization, and is remodeled in heart failure. KCNJ2 encodes the ion channel Kir2.1 that forms the
dominant protein pore subunit for IK1 in the human cardiac ventricle. Loss of function KCNJ2 mutations present
with two clinical phenotypes, Adersen-Tawil Syndrome (ATS), composed of a triad of ventricular arrhythmias,
dysmorphic features and periodic paralysis, or Catecholaminergic Polymorphic Ventricular Tachycardia
(CPVT), which presents with adrenergic-dependent ventricular arrhythmias including polymorphic ventricular
tachycardia (PMVT) and bidirectional VT (BiVT) with a lack non-cardiac ATS features. CPVT has been
attributed to abnormal calcium (Ca2+) handling related to mutations in Ca2+ handling genes and the signature
arrhythmia for CPVT, BiVT, is caused by Ca2+ overload. Unlike the other CPVT targets, Kir2.1 does not directly
participate in Ca2+ homeostasis, yet Ca2+ modulates Kir2.1 by specifically blocking the outward Kir2.1 current.
-adrenergic stimulation activates protein-kinase A (PKA), which phosphorylates Kir2.1 with subsequent
increase in outward Kir2.1 current. How Kir2.1 with CPVT-causing mutations fail to respond to PKA is
unknown, particularly since the known CPVT mutations are not phosphorylation sites. Our central hypothesis is
that under -adrenergic stimulation, CPVT-causing Kir2.1 mutant channels have loss of outward current due to
both lack of a PKA response and increased sensitivity to Ca2+ block, reducing outward current and thus
repolarization drive causing membrane potential instability, favoring delayed after-depolarizations (DADs)
triggered activity. Additionally, decreased IK1 in systolic heart failure is thought to be a key feature in ventricular
arrhythmias and SCD. We hypothesize that IK1 is decreased predominately during -adrenergic stimulation due
to elevated Ca2+ in a manner similar to CPVT-causing KCNJ2 mutations. In this study, we will address these
questions using a variety of cellular models and transgenic mouse models to determine the biophysical
properties, Ca2+ sensitivity, phosphorylation state and arrhythmia mechanism of KCNJ2 mutations associated
with a CPVT or an ATS phenotype and compare that to a heart failure model. Our innovative methods will
include high-definition mass spectrometry, optical mapping and calcium imaging. The outcomes of this
research will allow us to elucidate the mechanism by which -adrenergic-dependent loss of IK1 can result in
ventricular arrhythmia in CPVT and heart failure and compare that to an ATS arrhythmia mechanism.
Elucidating the nuances of IK1 dysfunction and Ca2+ handling under -adrenergic stress will lead to more
evidence-based treatment approaches and prevention of SCD.
心律失常性心源性猝死(SCD)是美国的主要死亡原因,可由以下因素引起
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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Lee Lochbaum Eckhardt其他文献
Lee Lochbaum Eckhardt的其他文献
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{{ truncateString('Lee Lochbaum Eckhardt', 18)}}的其他基金
Multiomics and Functional Characterization Establish Druggable Targets for PVC-Driven Idiopathic VF
多组学和功能表征为 PVC 驱动的特发性心室颤动建立药物靶标
- 批准号:
10750784 - 财政年份:2023
- 资助金额:
$ 38.12万 - 项目类别:
Deep Mutational Scanning and Functional Analysis of Repolarization Determinants
复极化决定因素的深度突变扫描和功能分析
- 批准号:
10599287 - 财政年份:2022
- 资助金额:
$ 38.12万 - 项目类别:
Deep Mutational Scanning and Functional Analysis of Repolarization Determinants
复极化决定因素的深度突变扫描和功能分析
- 批准号:
10467096 - 财政年份:2022
- 资助金额:
$ 38.12万 - 项目类别:
KCNJ2-Induced Arrhythmia Mechanisms in CPVT and Heart Failure.
KCNJ2 诱导 CPVT 和心力衰竭的心律失常机制。
- 批准号:
10228058 - 财政年份:2018
- 资助金额:
$ 38.12万 - 项目类别:
Arrhythmia Mechanisms from Inherited and Acquired Caveolin3 Dysregulation of IK1
IK1 遗传性和获得性 Caveolin3 失调引起的心律失常机制
- 批准号:
9100905 - 财政年份:2015
- 资助金额:
$ 38.12万 - 项目类别:
Arrhythmia Mechanisms from Inherited and Acquired Caveolin3 Dysregulation of IK1
IK1 遗传性和获得性 Caveolin3 失调引起的心律失常机制
- 批准号:
9243303 - 财政年份:2015
- 资助金额:
$ 38.12万 - 项目类别:
Training Program in Translational Cardiovascular Science
转化心血管科学培训项目
- 批准号:
10270772 - 财政年份:2001
- 资助金额:
$ 38.12万 - 项目类别:
Training Program in Translational Cardiovascular Science
转化心血管科学培训计划
- 批准号:
10687983 - 财政年份:2001
- 资助金额:
$ 38.12万 - 项目类别:
Training Program in Translational Cardiovascular Science
转化心血管科学培训项目
- 批准号:
10382467 - 财政年份:2001
- 资助金额:
$ 38.12万 - 项目类别:
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