The Structural Basis of Antiarrhythmic Drug Binding in Voltage-gated Ion Channels
The Structural Basis of Antiarrhythmic Drug Binding in Voltage-gated Ion Channels
批准号:
10558582
负责人:
MICHAEL J LENAEUS
金额:
$16.31万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-02-01 至 2024-01-31
关键词:
AffectAmericanAnti-Arrhythmia AgentsAreaArrhythmiaBindingBiological ModelsCalcium ChannelCalcium Channel BlockersCardiacChemistryChimera organismClinicalComplexCouplingCryoelectron MicroscopyCrystallizationDataDedicationsDevelopmentDiltiazemDiseaseDrug Binding SiteDrug PrescriptionsDrug Side EffectsElectrolytesElectrophysiology (science)FlecainideFutureGene MutationGoalsHealth ExpendituresHeartHeart AtriumHeart DiseasesHumanInheritedIon ChannelIon Channel GatingLidocaineMentorsMethodsModelingMolecularMolecular Mechanisms of ActionMorbidity - disease rateMyocardiumNatureNervous System PhysiologyPathway interactionsPharmaceutical PreparationsPharmacologyPhysiologyProteinsResearchResolutionSafetySiteSodium ChannelSodium Channel BlockersStructural ModelsStructureTechniquesTestingVentricular ArrhythmiaVisualizationWorkX-Ray Crystallographyclinically relevantdesigndrug actiondrug developmentexperimental studyhuman diseaseimprovedinsightmortalitynovelnovel therapeuticsprotein complexsuccesstherapeutically effectivevoltage
中文摘要
摘要/项目摘要
心律失常影响着数百万美国人,是一种常见的病因
老年美国人的发病率和死亡率,以及医疗保健
支出。它们有很多原因,包括遗传基因突变,
电解质紊乱和药物副作用--尽管所有这些原因都有共同之处
心肌电压门控离子通道失灵。抗心律失常
药物(AAD)被广泛用于治疗房性和室性心律失常。
阻止这样的渠道,尽管目前对
在结构水平上的分子作用机制。在这项提议中,我的目标是
为了研究电压门控钠钙通道模型中的AADS,使用
广泛使用的钠通道阻滞剂AAD利多卡因和氟卡胺以及
广泛使用的钙通道阻滞剂和地尔硫卓。我将使用已建立的
电生理学和X射线结晶学技术在AAD研究中的应用
具有细菌电压门控钠和钙通道的复合体,而
致力于建立AAD结合位点的新结构模型
串联细菌通道、高阶通道和冷冻-EM方法。我
希望这些实验能够更好地理解电压门控离子
渠道生理学和帮助设计更安全、更有效的AAD
作为一种可用于治疗房室疾病的新疗法
心律不齐。
英文摘要
Abstract/Project Summary
Cardiac arrhythmias affect millions of Americans and are a common cause
of morbidity and mortality in older Americans, as well as health care
expenditures. They have many causes including inherited gene mutations,
electrolyte disturbances, and drug side effects—though all of these causes share
the misfiring of voltage-gated ion channels in myocardium. Anti-arrhythmic
drugs (AAD) are widely used to treat both atrial and ventricular arrhythmias by
blocking such channels, though there is currently a limited understanding of the
AAD molecular mechanism of action on a structural level. In this proposal, I aim
to study AADs in model voltage-gated sodium and calcium channels, using the
widely used sodium channel blocker AAD lidocaine and flecainide as well as the
widely used calcium channel blocker AAD diltiazem. I will use established
techniques of electrophysiology and X-ray crystallography to study AAD in
complex with bacterial voltage-gated sodium and calcium channels, while
working to establish new structural models of the AAD binding site using
concatenated bacterial channels, higher order channels, and Cryo-EM methods. I
expect these experiments to allow for a better understanding of voltage-gated ion
channel physiology and aid in the design of safer and more effective AAD, as well
as novel therapeutics that may be used for treatment of atrial and ventricular
arrhythmias.
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会议论文
Structural Basis of Potassium Channel Drug Interactions
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批准号:7414410
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项目类别:
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资助金额:$2.74万
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财政年份:2007
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负责人:MICHAEL J LENAEUS
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依托单位:
Structural Basis of Potassium Channel Drug Interactions
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批准号:7156561
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项目类别:
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资助金额:$3.04万
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财政年份:2007
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负责人:MICHAEL J LENAEUS
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依托单位:
Structural Basis of Potassium Channel Drug Interactions
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批准号:7628954
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项目类别:
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资助金额:$2.76万
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财政年份:2007
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负责人:MICHAEL J LENAEUS
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依托单位:
海外基金