NO signaling by a Soluble Guanylyl Cyclase -Thioredoxin transnitrosation complex
可溶性鸟苷酸环化酶-硫氧还蛋白转亚硝基复合物的 NO 信号传导
基本信息
- 批准号:10580267
- 负责人:
- 金额:$ 8.66万
- 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 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAdenovirusesAdministrative SupplementAffectAngiotensin IIApoptosisBindingBiochemicalBioinformaticsBiological AssayBlood VesselsCRISPR/Cas technologyCalciumCardiacCardiovascular systemCell LineCell physiologyCellsCo-ImmunoprecipitationsComplexConsensusCyclic GMPCysteineEnvironmentEquilibriumEquipmentFunctional disorderFundingGuanosine TriphosphateHeart HypertrophyHeart failureHomeostasisHypertensionImpairmentInvestigationKnock-inKnock-in MouseLeadLigationMass Spectrum AnalysisMeasuresMediator of activation proteinMetabolic PathwayModelingModificationMusMutation AnalysisNitric OxideNitrosationOLFM4 geneOxidation-ReductionOxidative StressOxidesPathologicPathway interactionsPeptidesPhysiologicalPost-Translational Protein ProcessingPropertyProteinsProteomicsRegulationRoleSKIL geneSignal PathwaySignal TransductionSignaling MoleculeSiteSkeletonSmooth MuscleSoluble Guanylate CyclaseSpecificityStressSulfhydryl CompoundsSystemTXN geneTechnologyVasodilationWild Type Mouseangiogenesisblood pressure regulationcGMP productioncardioprotectiondesensitizationheme aimprovedin vivointravital microscopymouse modelnoveloxidationparent grantpolymerizationpressureprotective effectprotein functionprotein protein interactionresponse
项目摘要
PROJECT SUMMARY (PARENT GRANT)
This is an application for an administrative supplemental equipment under our parent grant GM112415. The
equipment we are requesting is at the center of our experimental strategy. This equipment is a Pressure
Myograph P114 system that will replace and upgrade an intravital microscopy system that is not anymore
available to us. We will not be able to complete Aim3 without this type of equipment and because of the upgraded
technology we will improve and expand the investigations of Aim1 and Aim2 of the project of our parent grant
summarized below:
Nitric oxide (NO) is an important signaling molecule that regulates diverse functions relevant to vascular function,
apoptosis and angiogenesis. NO is best known for its ability to stimulate soluble guanylyl cyclase (now called
GC1) to produce cGMP and stimulate its downstream signaling pathways. However, NO can also covalently
modify cysteines (Cys) via S-nitrosation or S-nitrosylation (addition of a NO moiety to the cysteine of a protein,
SNO). Although this reversible post-translational modification is increasingly recognized as an important
regulatory mechanism of protein function, dynamic regulation of protein nitrosation specificity is poorly
understood. Our most recent investigations reveal that GC1 has a transnitrosylase activity, i.e. GC1 has the
ability to directly transfer SNO to specific targets by protein-protein interaction (transnitrosation). This
transnitrosation activity does not require the cGMP forming activity of GC1 and can be accomplished by a single
subunit of GC1 (formation of cGMP requires 2 subunits). Furthermore, we showed that one transnitrosation
target of GC1 is oxidized thioredoxin 1 (oTrx1), a thiol-redox protein that modulates cellular S-nitrosation. In fact,
oxidative/nitrosative conditions appear to favor the GC1-Trx1 complex. Using advanced proteomics approaches,
we recently identified the Cys in GC1 and Trx1 that are involved in the SNO transfer in a purified system, and
the Cys of proteins targeted by the GC1/Trx1 transnitrosation cascade in smooth muscle and cardiac cells. Our
hypothesis is that the function of GC1 transnitrosation activity is an adaptive response to oxidative stress and
potentially compensates for the dysfunction of the canonical NO-GC1-cGMP pathway that occurs in oxidative
conditions. To explore this provocative hypothesis, we propose to conduct mutational analysis of the Cys we
have identified to characterize the mechanism of transnitrosation in smooth muscle and cardiac cells. By
comparing the targets of GC1, Trx1 and both we will determine the mechanisms underlying target specificity.
We will determine how GC1/Trx1 transnitrosation of specific targets affects their cellular function. For this, we
will use cell lines and primary cells isolated from a novel mouse knock-in (KI) of a Cys of GC1 involved in
transnitrosation. To determine the physiological relevance of GC1- and GC1/Trx1-transnitrosation in the
cardiovascular system and the adaptive response to stress, we will use the Cys KI mouse model and inhibitory
peptides that disrupt the GC1/Trx1 transnitrosating complex under Angiotensin II-induced oxidative stress. This
project could lead to the discovery of novel cardiovascular protective pathways driven by specific S-nitrosation.
项目摘要(家长资助)
这是我们的母基金 GM112415 下的行政补充设备申请。这
我们要求的设备是我们实验策略的核心。该设备是压力
Myograph P114 系统将取代和升级已不再存在的活体显微镜系统
可供我们使用。如果没有这种类型的设备,我们将无法完成 Aim3,因为升级后的
我们将改进和扩大我们母基金项目的 Aim1 和 Aim2 的调查
总结如下:
一氧化氮(NO)是一种重要的信号分子,可调节与血管功能相关的多种功能,
细胞凋亡和血管生成。 NO 以其刺激可溶性鸟苷酸环化酶(现称为
GC1) 产生 cGMP 并刺激其下游信号通路。然而,NO 也可以共价
通过 S-亚硝化或 S-亚硝基化修饰半胱氨酸 (Cys)(在蛋白质的半胱氨酸上添加 NO 部分,
斯诺)。尽管这种可逆的翻译后修饰越来越被认为是一种重要的
蛋白质功能的调控机制,蛋白质亚硝化的动态调控特异性较差
明白了。我们最近的研究表明GC1具有转亚硝基酶活性,即GC1具有
通过蛋白质-蛋白质相互作用(转亚硝化)将 SNO 直接转移至特定靶标的能力。这
转亚硝化活性不需要GC1的cGMP形成活性,并且可以通过单一的
GC1 的亚基(cGMP 的形成需要 2 个亚基)。此外,我们还发现一种转亚硝基
GC1 的靶标是氧化硫氧还蛋白 1 (oTrx1),这是一种调节细胞 S-亚硝化的硫醇氧化还原蛋白。实际上,
氧化/亚硝化条件似乎有利于 GC1-Trx1 复合物。使用先进的蛋白质组学方法,
我们最近在纯化系统中鉴定了 GC1 和 Trx1 中参与 SNO 转移的 Cys,并且
平滑肌和心肌细胞中 GC1/Trx1 转亚硝基级联反应所靶向的蛋白质的 Cys。我们的
假设GC1转亚硝基活性的功能是对氧化应激的适应性反应
潜在地补偿氧化过程中发生的典型 NO-GC1-cGMP 途径的功能障碍
状况。为了探索这一具有争议性的假设,我们建议对我们研究的半胱氨酸进行突变分析。
已经确定了平滑肌和心肌细胞中转亚硝化机制的特征。经过
通过比较 GC1、Trx1 和两者的靶标,我们将确定靶标特异性的潜在机制。
我们将确定特定靶标的 GC1/Trx1 转亚硝基作用如何影响其细胞功能。为此,我们
将使用从涉及 GC1 的 Cys 的新型小鼠敲入 (KI) 中分离的细胞系和原代细胞
转亚硝化。确定 GC1- 和 GC1/Trx1-转亚硝基作用在
心血管系统和对压力的适应性反应,我们将使用Cys KI小鼠模型和抑制
在血管紧张素 II 诱导的氧化应激下破坏 GC1/Trx1 转亚硝基复合物的肽。这
该项目可能会发现由特定 S-亚硝化驱动的新型心血管保护途径。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ANNIE V BEUVE其他文献
ANNIE V BEUVE的其他文献
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{{ truncateString('ANNIE V BEUVE', 18)}}的其他基金
NO signaling by a Soluble Guanylyl Cyclase -Thioredoxin transnitrosation complex
可溶性鸟苷酸环化酶-硫氧还蛋白转亚硝基复合物的 NO 信号传导
- 批准号:
10680605 - 财政年份:2015
- 资助金额:
$ 8.66万 - 项目类别:
NO signaling by a Soluble Guanylyl Cyclase-Thioredoxin transnitrosation complex
可溶性鸟苷酸环化酶-硫氧还蛋白转亚硝基复合物的 NO 信号转导
- 批准号:
8894270 - 财政年份:2015
- 资助金额:
$ 8.66万 - 项目类别:
NO signaling by a Soluble Guanylyl Cyclase -Thioredoxin transnitrosation complex
可溶性鸟苷酸环化酶-硫氧还蛋白转亚硝基复合物的 NO 信号传导
- 批准号:
10475129 - 财政年份:2015
- 资助金额:
$ 8.66万 - 项目类别:
NO signaling by a Soluble Guanylyl Cyclase -Thioredoxin transnitrosation complex
可溶性鸟苷酸环化酶-硫氧还蛋白转亚硝基复合物的 NO 信号传导
- 批准号:
10260574 - 财政年份:2015
- 资助金额:
$ 8.66万 - 项目类别:
NO signaling by a Soluble Guanylyl Cyclase -Thioredoxin transnitrosation complex
可溶性鸟苷酸环化酶-硫氧还蛋白转亚硝基复合物的 NO 信号传导
- 批准号:
10119473 - 财政年份:2015
- 资助金额:
$ 8.66万 - 项目类别:
S-nitrosylation of soluble guanylyl cyclase: potential role in nitrate tolerance
可溶性鸟苷酸环化酶的 S-亚硝基化:在硝酸盐耐受性中的潜在作用
- 批准号:
7620065 - 财政年份:2008
- 资助金额:
$ 8.66万 - 项目类别:
S-nitrosylation of soluble guanylyl cyclase: potential role in nitrate tolerance
可溶性鸟苷酸环化酶的 S-亚硝基化:在硝酸盐耐受性中的潜在作用
- 批准号:
7472094 - 财政年份:2008
- 资助金额:
$ 8.66万 - 项目类别:
Regulation of Soluble guanylyl cyclase, the NO-receptor
可溶性鸟苷酸环化酶(NO 受体)的调节
- 批准号:
7217328 - 财政年份:2003
- 资助金额:
$ 8.66万 - 项目类别:
Regulation of Soluble Guanylyl Cyclase, the NO-Receptor
可溶性鸟苷酸环化酶(NO 受体)的调节
- 批准号:
8636026 - 财政年份:2003
- 资助金额:
$ 8.66万 - 项目类别:
Regulation of Soluble Guanylyl Cyclase, the NO-Receptor
可溶性鸟苷酸环化酶(NO 受体)的调节
- 批准号:
7596175 - 财政年份:2003
- 资助金额:
$ 8.66万 - 项目类别:
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