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.
心律失常性心脏性猝死(SCD)是美国主要的死亡原因,可由以下因素引起
遗传性心律失常综合征或获得性心脏病(如心脏)中的离子电流异常
失败了。本课题主要研究心脏内向整流电流(Ik1)对肾上腺素能依赖性的影响。
遗传性和获得性室性心律失常。IK1维持静息膜电位,参与第三相
复极,并在心力衰竭时重塑。KCNJ2编码离子通道Kir2.1,它形成了
人心室中IK1的主要蛋白孔亚基。存在功能丧失的KCNJ2突变
有两种临床表型,Adersen-Tawil综合征(ATS),由三组室性心律失常组成,
畸形特征和周期性瘫痪,或儿茶酚胺能多形性室性心动过速
(CPVT),表现为肾上腺素能依赖性室性心律失常,包括多形性室性心律失常
心动过速(PMVT)和双向室速(BiVT)缺乏非心源性ATS特征。CPVT一直是
归因于与钙离子调控基因突变相关的异常钙离子调控及其特征
CPVT,BiVT的心律失常是由钙超载引起的。与其他CPVT目标不同,Kir2.1不直接
参与钙离子动态平衡,但钙离子通过特异性地阻断外向Kir2.1电流来调节Kir2.1。
-肾上腺素能刺激激活蛋白激酶A,使kir2.1与随后的
增加向外基尔2.1的电流。导致CPVT突变的Kir2.1是如何对PKA没有反应的
未知,特别是因为已知的CPVT突变不是磷酸化位点。我们的中心假设是
在-肾上腺素能刺激下,引起慢性静脉曲张的Kir2.1突变通道的外向电流损失是由于
两者都缺乏PKA反应和对钙离子阻断的敏感性增加,从而减少外向电流,从而
复极驱动导致膜电位不稳定,有利于延迟后除极(DAD)
触发了活动。此外,收缩性心力衰竭时IK1降低被认为是室性心衰的一个关键特征。
心律失常和SCD。我们假设,在-肾上腺素能刺激过程中,Ik1主要降低
以类似于CPVT引起的KCNJ2突变的方式升高钙离子。在这项研究中,我们将解决这些问题
问题:使用各种细胞模型和转基因小鼠模型来确定生物物理
KCNJ2基因突变的性质、钙敏感性、磷酸化状态及心律失常机制
CPVT或ATS表型,并将其与心力衰竭模型进行比较。我们的创新方法将
包括高清晰度质谱学、光学测绘和钙成像。这样做的结果是
研究将使我们能够阐明-肾上腺素能依赖的IK1丢失导致
CPVT和心力衰竭的室性心律失常,并与ATS的心律失常机制进行比较。
阐明-肾上腺素能应激下IK1功能障碍和钙处理的细微差别将导致更多
SCD的循证治疗方法和预防。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Lee Lochbaum Eckhardt其他文献
Lee Lochbaum Eckhardt的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 38.12万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 38.12万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 38.12万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 38.12万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 38.12万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 38.12万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 38.12万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 38.12万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 38.12万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 38.12万 - 项目类别:
Research Grant