S-Nitrosylation and Cardioprotection
S-亚硝基化和心脏保护
基本信息
- 批准号:9015474
- 负责人:
- 金额:$ 24.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-23 至 2018-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectBindingCardiac MyocytesCause of DeathCell NucleusCysteineCytosolDataFellowshipGoalsHealthcareHeartIn SituInterventionIon ChannelKnowledgeLeadMediatingMethodsMitochondriaMitochondrial MatrixModelingModificationMolecularMorbidity - disease rateMutagenesisMyocardialMyocardial IschemiaMyocardial dysfunctionMyocardiumNOS3 geneNitric OxideNitric Oxide SynthaseNitric Oxide Synthase Type IPathologicPhysiologicalPlayPostdoctoral FellowProductionProtein IsoformsProtein SProtein translocationProteinsRegulationReperfusion InjuryResearchRoleSignal PathwaySignal TransductionSiteSourceSpecificityStimulusSulfhydryl CompoundsTestingTherapeuticTranslatingUnited Statesbaseextracellularinsightmortalitymutantnoveloxidationprotective effectprotein functionprotein protein interactionresearch studytherapeutic target
项目摘要
PROJECT SUMMARY/ABSTRACT
Ischemic heart disease is one of the most common causes of death in the United States and is responsible for
a tremendous healthcare burden. Cardioprotective interventions hold great promise for lessening this burden,
but few experimental discoveries have translated successfully into effective therapeutics. This is likely due to a
lack of knowledge with regard to the mechanistic details of cardioprotection. Nitric oxide, either produced
endogenously or administered exogenously, has been shown to be an important component of
cardioprotection. Our recent studies have demonstrated an association between increased levels of nitric
oxide-derived protein S-nitrosylation and cardioprotection. S-nitrosylation is a reversible, thiol-based
modification that is produced from the covalent attachment of a nitric oxide moiety to the free thiol group of a
cysteine residue. The nitric oxide synthase isoforms represent the major source of endogenous nitric oxide
production in the cardiac myocyte. S-nitrosylation is thought to provide protective effects by modulating the
activity and/or function of target proteins, and by blocking the damaging effects of irreversible cysteine
oxidation. Our recent data are consistent with an overall protective role for S-nitrosylation, but the molecular
mechanism(s), the relative importance of specific protein targets, and the pathophysiological significance of S-
nitrosylation is unknown. Thus, the goal of this proposal is to define the specificity and mechanistic
consequences of protein S-nitrosylation in the myocardium by investigating the physiologic and pathologic
aspects of S-nitrosylation. To establish the mechanistic details of S-nitrosylation, a novel method to determine
the percentage of a given protein that is modified by S-nitrosylation (i.e., S-nitrosylation occupancy) is being
developed and this will be used to examine compartmentalized S-nitrosylation signaling. Cysteine mutagenesis
will also be used to examine the effects of S-nitrosylation on protein function. We previously identified many S-
nitrosylation sites in cardioprotection, thus allowing us to focus on specific cysteine residues that are altered in
situ. The specific aims of this proposal are as follows: 1) determine if S-nitrosylation occupancy varies between
different cellular compartments of the cardiomyocyte and evaluate how this affects signaling, 2) determine if S-
nitrosylation changes protein-protein interaction, alters protein localization, and promotes protein trans-S-
nitrosylation, and 3) determine the specific role of S-nitrosylation in the regulation of myocardial ion channel
activity. The results of this proposal will define the role of S-nitrosylation in the heart and advance the field by
establishing a mechanistic role for S-nitrosylation, thus lending critical insight into potential therapeutic targets.
项目总结/摘要
缺血性心脏病是美国最常见的死亡原因之一,
巨大的医疗负担。预防性干预措施对减轻这一负担大有希望,
但很少有实验发现成功地转化为有效的治疗方法。这很可能是由于
缺乏关于心脏保护机制细节的知识。一氧化氮,无论是产生
内源性或外源性给药,已被证明是
心脏保护我们最近的研究表明,一氧化氮水平的增加
氧化衍生蛋白S-亚硝基化和心脏保护。S-亚硝基化是一种可逆的,基于硫醇的
修饰是由一氧化氮部分共价连接到一氧化氮的游离巯基上而产生的。
半胱氨酸残基。一氧化氮合酶亚型代表内源性一氧化氮的主要来源
在心肌细胞中产生。S-亚硝基化被认为通过调节细胞内的
靶蛋白的活性和/或功能,以及通过阻断不可逆半胱氨酸的损伤作用
氧化我们最近的数据与S-亚硝基化的总体保护作用一致,但分子水平
机制,特定蛋白质靶点的相对重要性,以及S-
亚硝基化是未知的。因此,本提案的目标是确定
蛋白质S-亚硝基化在心肌中的后果,通过研究生理和病理
S-亚硝基化方面。为了建立S-亚硝基化的机理细节,一种新的方法来确定
通过S-亚硝基化修饰的给定蛋白质的百分比(即,S-亚硝基化占据)正在
开发,这将用于检查区室化的S-亚硝基化信号传导。半胱氨酸诱变
也将用于检查S-亚硝基化对蛋白质功能的影响。我们之前发现了很多S-
亚硝基化位点在心脏保护中的作用,从而使我们能够专注于特定的半胱氨酸残基,
原地。该建议的具体目标如下:1)确定S-亚硝基化占据是否在以下之间变化:
心肌细胞的不同细胞区室,并评估这如何影响信号传导,2)确定S-
亚硝基化改变蛋白质-蛋白质相互作用,改变蛋白质定位,并促进蛋白质trans-S-
确定S-亚硝基化在心肌离子通道调节中的特殊作用
活动该提案的结果将定义S-亚硝基化在心脏中的作用,并通过以下方式推进该领域:
建立了S-亚硝基化的机制作用,从而为潜在的治疗靶点提供了重要的见解。
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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Mark Jeffrey Kohr其他文献
Mark Jeffrey Kohr的其他文献
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{{ truncateString('Mark Jeffrey Kohr', 18)}}的其他基金
Role of formaldehyde, formate and one-carbon metabolism in the female heart
甲醛、甲酸盐和一碳代谢在女性心脏中的作用
- 批准号:
10193514 - 财政年份:2021
- 资助金额:
$ 24.3万 - 项目类别:
Role of formaldehyde, formate and one-carbon metabolism in the female heart
甲醛、甲酸盐和一碳代谢在女性心脏中的作用
- 批准号:
10471171 - 财政年份:2021
- 资助金额:
$ 24.3万 - 项目类别:
S-nitrosation in cell survival and cell death
S-亚硝化在细胞存活和细胞死亡中的作用
- 批准号:
10308396 - 财政年份:2017
- 资助金额:
$ 24.3万 - 项目类别:
Role of protein S-nitrosation in cardioprotection
蛋白质S-亚硝化在心脏保护中的作用
- 批准号:
7883631 - 财政年份:2009
- 资助金额:
$ 24.3万 - 项目类别:
Role of protein S-nitrosation in cardioprotection
蛋白质S-亚硝化在心脏保护中的作用
- 批准号:
7670691 - 财政年份:2009
- 资助金额:
$ 24.3万 - 项目类别:
Role of protein S-nitrosation in cardioprotection
蛋白质S-亚硝化在心脏保护中的作用
- 批准号:
8085866 - 财政年份:2009
- 资助金额:
$ 24.3万 - 项目类别:
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