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)
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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{{ 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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