KATP Channel Trafficking and Cardioprotection
KATP 通道运输和心脏保护
基本信息
- 批准号:9236252
- 负责人:
- 金额:$ 7.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAdenosineAdultArrhythmiaBackBiological AssayBiotinylationC-terminalCardiacCardiac MyocytesCause of DeathCell modelCell physiologyCellsCessation of lifeComplexConfocal MicroscopyCoupledDataDefectDependenceDeveloped CountriesDominant-Negative MutationElementsEndocytosisEventFamily memberFunctional disorderGLUT4 geneHealthHeartHeart DiseasesHeart RateInfarctionInjuryIschemiaIschemic PreconditioningKnock-outKnockout MiceMass Spectrum AnalysisMeasurementMediator of activation proteinMembrane ProteinsMetabolicMolecularMusMuscle CellsMutagenesisMyocardial IschemiaMyocardiumPathway interactionsPatternPhysiologicalProtein FamilyProtein KinaseProteinsPumpReactive Oxygen SpeciesRecyclingReperfusion TherapyResearchRoleSignal PathwaySpecificityStressSurfaceTamoxifenTertiary Protein StructureTranscription Factor AP-2 AlphaTransgenic MiceUnited StatesVentricularconditioningdensitydesignextracellularheart rhythminhibitor/antagonistinsightmouse modelnew therapeutic targetnoveloverexpressionpatch clamppreventprotective effecttherapeutic developmenttrafficking
项目摘要
DESCRIPTION (provided by applicant): Heart disease remains the leading cause of death in the United States and other developed countries. Most deaths are associated with cardiac ischemia and arrhythmias. Sarcolemmal KATP channels in the myocardium open with elevated heart rates and during stress conditions, such as cardiac ischemia. Opening of KATP channels modulate the action potential duration and intracellular Ca2+. As such they have an important role in determining contractility, arrhythmias and electrical conduction. It is well established tht KATP channel opening protects the heart during stress. However, a detailed understanding of the KATP channel function during ischemia, reperfusion and ischemic preconditioning is lacking, which hinders the development of therapeutic strategies. Our preliminary data point to novel subcellular localization patterns of KATP channels within the cardiac myocyte. We further find that myocardial ischemia decreases the surface KATP channel density, which reduces the number of channels that are available for cardioprotection. This proposal is driven by our preliminary observations that a) ischemic preconditioning prevents ischemia-induced internalization of KATP channels and that b) the protective effects of ischemic preconditioning on infarct size are abolished in mice with cardiac-specific knockout of the KATP channel subunit, Kir6.2. We hypothesize that enhancing KATP channel surface density through specific subcellular trafficking pathways is an important element of the protective mechanism of ischemic preconditioning. We will investigate molecular mechanisms that stabilize surface KATP channels (Aim 1), cellular processes that regulate internalization (Aim 2) and potential mechanisms to restore the KATP channel surface density during an ischemic insult (Aim 3). The proposed studies will establish a framework in which to understand novel roles of KATP channels in the heart and will provide molecular insights their cardioprotective function during ischemic pre-conditioning.
描述(由适用提供):心脏病仍然是美国和其他发达国家的主要死亡原因。大多数死亡都与心脏缺血和心律不齐有关。心肌开放的肌膜KATP通道,心率升高和压力条件(例如心脏缺血)。 KATP通道的打开调节动作电位持续时间和细胞内Ca2+。因此,它们在确定收缩力,心律不齐和电导传导方面具有重要作用。它已经建立了良好的KATP通道开放可以在压力下保护心脏。但是,缺乏缺血,再灌注和缺血性预处理期间KATP通道功能的详细理解,这阻碍了理论策略的发展。我们的初步数据指向心肌细胞中KATP通道的新型亚细胞定位模式。我们进一步发现,心肌缺血降低了表面KATP通道密度,从而减少了可用于心脏保护的通道数量。该提案是由我们的初步观察驱动的:a)缺血性预处理阻止缺血诱导的KATP通道内在化,并且b)b)在具有KATP通道亚基katp Channel unitit,Kir6.2的心脏特异性敲除小鼠中,缺血性预处理对梗塞大小的受保护作用被废除。我们假设通过特定的亚细胞运输途径增强KATP通道表面密度是缺血性预处理机制的重要元素。我们将研究稳定表面KATP通道的分子机制(AIM 1),调节内在化的细胞过程(AIM 2)以及在缺血性损伤过程中恢复KATP通道表面密度的潜在机制(AIM 3)。拟议的研究将建立一个框架,在该框架中,了解KATP通道在心脏中的新作用,并将在缺血性预处理期间提供分子见解其心脏保护功能。
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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William A Coetzee其他文献
William A Coetzee的其他文献
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{{ truncateString('William A Coetzee', 18)}}的其他基金
Roles of Endothelial and Smooth Muscle KATP Channels in Myocardial Ischemic Injury
内皮和平滑肌 KATP 通道在心肌缺血性损伤中的作用
- 批准号:
10839729 - 财政年份:2023
- 资助金额:
$ 7.94万 - 项目类别:
Tweety proteins: their roles in pericytes and macrophages
Tweety 蛋白:它们在周细胞和巨噬细胞中的作用
- 批准号:
10665494 - 财政年份:2023
- 资助金额:
$ 7.94万 - 项目类别:
Functional interaction between cardiac Na channels and KATP channels
心脏 Na 通道和 KATP 通道之间的功能相互作用
- 批准号:
10160950 - 财政年份:2020
- 资助金额:
$ 7.94万 - 项目类别:
Functional interaction between cardiac Na channels and KATP channels
心脏 Na 通道和 KATP 通道之间的功能相互作用
- 批准号:
10399543 - 财政年份:2020
- 资助金额:
$ 7.94万 - 项目类别:
Functional interaction between cardiac Na channels and KATP channels
心脏 Na 通道和 KATP 通道之间的功能相互作用
- 批准号:
10613516 - 财政年份:2020
- 资助金额:
$ 7.94万 - 项目类别:
Roles of Endothelial and Smooth Muscle KATP Channels in Myocardial Ischemic Injury
内皮和平滑肌 KATP 通道在心肌缺血性损伤中的作用
- 批准号:
9914670 - 财政年份:2019
- 资助金额:
$ 7.94万 - 项目类别:
Roles of Endothelial and Smooth Muscle KATP Channels in Myocardial Ischemic Injury
内皮和平滑肌 KATP 通道在心肌缺血性损伤中的作用
- 批准号:
10308702 - 财政年份:2019
- 资助金额:
$ 7.94万 - 项目类别:
Roles of Endothelial and Smooth Muscle KATP Channels in Myocardial Ischemic Injury
内皮和平滑肌 KATP 通道在心肌缺血性损伤中的作用
- 批准号:
10064008 - 财政年份:2019
- 资助金额:
$ 7.94万 - 项目类别:
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