Nitrosylation Mechanisms for Protection Against Neurovascular Inflammatory Injury
预防神经血管炎症损伤的亚硝基化机制
基本信息
- 批准号:8652841
- 负责人:
- 金额:$ 31.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-05-01 至 2016-04-30
- 项目状态:已结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAccidentsAmericanAnimal ModelArginineAthletic InjuriesBiological AvailabilityBlood - brain barrier anatomyBlood VesselsBrainDiffusionEdemaEndothelial CellsEndotheliumEngineered GeneEnzymesEventExtravasationFigs - dietaryGeneticGlutathioneImpairmentInflammationInflammatoryInjuryInterventionIschemiaKnockout MiceLeadMediatingMediator of activation proteinModelingModificationMusNecrosisNeuronsNitric OxideNitric Oxide DonorsNitrogenOxygenPathway interactionsPeroxonitritePhosphorylationProcessProductionReactionRecovery of FunctionRegulationReperfusion TherapyReportingRoleS-NitrosoglutathioneSTK11 geneSignal TransductionStrokeSuperoxidesSupportive careTestingTherapeuticTransgenic MiceTraumatic Brain InjuryWarWild Type Mouseadenylate kinasebaseclinically relevantcofactorcontrolled cortical impacthuman NOS3 proteinin vivoinhibitor/antagonistmouse modelneurobehaviorneurobehavioralneuron lossneurovascular unitnovelpublic health relevancesuccesstetrahydrobiopterintooltreatment strategyupstream kinase
项目摘要
DESCRIPTION (provided by applicant): Brain trauma induces inflammation in both the endothelium and the brain parenchyma, collectively termed the neurovascular unit. While neurons die quickly by necrosis following traumatic brain injury (TBI), a vicious cycle of inflammation in endothelial cells exacerbates the injury. In activated endothelial cells, excessive superoxide reacts with nitric oxide (NO) to form peroxynitrite. At high levels following TBI, peroxynitrite is involved in blood brain barrier (BBB) leakage, altered enzymatic functions, and neurobehavior impairment. It activates AMP Kinase (AMPK), which in turn may up regulate the superoxide-producing activity of endothelial nitric oxide synthase (eNOS), and thus maintains a vicious cycle of neuroinflammatory secondary injury. The nitrosylating agent S-nitrosoglutathione (GSNO) is capable of reducing the levels of peroxynitrite and inhibiting the activity of AMPK. It also restores the levels of glutathione and protects the integrity of the neurovascular unit. Therefore, this study will investigate whether GSNO treatment ameliorates TBI-induced neuroinflammatory damage to the neurovascular unit via nitrosylation. We hypothesize that GSNO blocks the vicious AMPK/eNOS/peroxynitrite cycle, thus reducing the neurovascular injury and aiding functional recovery in TBI. In Specific Aim 1, pharmacological agents (GSNO, a peroxynitrite scavenger, and an AMPK selective inhibitor) will be used as therapeutic tools to dissect the regulation of AMPK and amelioration of TBI in a controlled cortical impact mouse model. In Specific Aim 2, the elucidated mechanisms will be further examined and validated using AMPK alpha 1/2 knockout mice, AMPK alpha over-expressing transgenic mice, and wild type mice. In Specific Aim 3, we will determine whether GSNO-mediated nitrosylation of either AMPK or its upstream kinase LKB1 is responsible for the inhibition of aberrant eNOS activity and the reduced formation of peroxynitrite. The complementary pharmacological and genetic approach will determine the role of AMPK in TBI. GSNO, unlike conventional NO donors, is a non-toxic endogenous NO modulator and nitrosylating agent. Understanding S-nitrosylation mechanism and the unique AMPK/eNOS/peroxynitrite pathway may lead to new strategies for the treatment of neuroinflammatory brain trauma that target not only its neuronal consequences but also its vascular causes and exacerbations.
描述(由申请人提供):脑外伤引起内皮和脑实质炎症,统称为神经血管单位。创伤性脑损伤(TBI)后神经元迅速坏死,内皮细胞炎症的恶性循环加剧了损伤。在活化的内皮细胞中,过量的超氧化物与一氧化氮(NO)反应形成过氧亚硝酸盐。脑外伤后高水平的过氧亚硝酸盐与血脑屏障(BBB)渗漏、酶功能改变和神经行为障碍有关。它激活AMP激酶(AMPK),进而上调内皮型一氧化氮合酶(eNOS)产生超氧化物的活性,从而维持神经炎症继发性损伤的恶性循环。亚硝基化剂s -亚硝基谷胱甘肽(GSNO)具有降低过氧亚硝酸盐水平和抑制AMPK活性的作用。它还恢复谷胱甘肽的水平,并保护神经血管单位的完整性。因此,本研究将探讨GSNO治疗是否通过亚硝基化改善tbi诱导的神经血管单元的神经炎症损伤。我们假设GSNO阻断了恶性AMPK/eNOS/过氧亚硝酸盐循环,从而减少了脑外伤的神经血管损伤,帮助功能恢复。在Specific Aim 1中,药理学药物(GSNO,过氧亚硝酸盐清除剂和AMPK选择性抑制剂)将被用作治疗工具,在受控皮质冲击小鼠模型中解剖AMPK的调节和TBI的改善。在Specific Aim 2中,我们将使用AMPK α 1/2敲除小鼠、AMPK α过表达转基因小鼠和野生型小鼠进一步检验和验证阐明的机制。在Specific Aim 3中,我们将确定gsno介导的AMPK或其上游激酶LKB1的亚硝基化是否对异常eNOS活性的抑制和过氧亚硝酸盐形成的减少负责。互补的药理学和遗传学方法将确定AMPK在TBI中的作用。与传统的NO供体不同,GSNO是一种无毒的内源性NO调节剂和亚硝基化剂。了解s -亚硝基化机制和独特的AMPK/eNOS/过氧亚硝酸盐途径可能为治疗神经炎性脑损伤提供新的策略,这些策略不仅针对其神经元后果,还针对其血管原因和恶化。
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)
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Avtar K Singh其他文献
LOW DOSE ZIDOVUDINE (ZDV) REDUCES MEDIUM AND LONG CHAIN FATTY ACID OXIDATION IN PREGNANT AND NEONATAL RATS. † 1033
- DOI:
10.1203/00006450-199604001-01055 - 发表时间:
1996-04-01 - 期刊:
- 影响因子:3.100
- 作者:
George M Johnson;Mahesh Gupta;Karl Krember;Avtar K Singh;Inderjit Singh - 通讯作者:
Inderjit Singh
FATPY ACID METABOLISM IN REYE'S SYNDROME
雷耶综合征中的脂肪酸代谢
- DOI:
10.1203/00006450-198704010-01003 - 发表时间:
1987-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Inderjit Singh;Yoshihiro Yoshida;Avtar K Singh;Fred W Mecklenberq;C P Darby - 通讯作者:
C P Darby
5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) attenuates the expression of LPS- and Aβ peptide-induced inflammatory mediators in astroglia
- DOI:
10.1186/1742-2094-2-21 - 发表时间:
2005-09-20 - 期刊:
- 影响因子:10.100
- 作者:
Kamesh R Ayasolla;Shailendra Giri;Avtar K Singh;Inderjit Singh - 通讯作者:
Inderjit Singh
Avtar K Singh的其他文献
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{{ truncateString('Avtar K Singh', 18)}}的其他基金
Mechanism of Vascular Impairment in Neurocognitive Disorders
神经认知障碍中血管损伤的机制
- 批准号:
10553093 - 财政年份:2021
- 资助金额:
$ 31.94万 - 项目类别:
Mechanism of Vascular Impairment in Neurocognitive Disorders
神经认知障碍中血管损伤的机制
- 批准号:
10343797 - 财政年份:2021
- 资助金额:
$ 31.94万 - 项目类别:
Development of S-Nitrosothiol-based Therapy for Alzheimer's Disease
基于 S-亚硝基硫醇的阿尔茨海默病疗法的开发
- 批准号:
8398957 - 财政年份:2011
- 资助金额:
$ 31.94万 - 项目类别:
Nitrosylation Mechanisms for Protection Against Neurovascular Inflammatory Injury
预防神经血管炎症损伤的亚硝基化机制
- 批准号:
8458156 - 财政年份:2011
- 资助金额:
$ 31.94万 - 项目类别:
Development of S-Nitrosothiol-based Therapy for Alzheimer's Disease
基于 S-亚硝基硫醇的阿尔茨海默病疗法的开发
- 批准号:
8141069 - 财政年份:2011
- 资助金额:
$ 31.94万 - 项目类别:
Nitrosylation Mechanisms for Protection Against Neurovascular Inflammatory Injury
预防神经血管炎症损伤的亚硝基化机制
- 批准号:
8259741 - 财政年份:2011
- 资助金额:
$ 31.94万 - 项目类别:
Mechanisms of Krabbe Disease Pathobiology and Therapy
克拉伯病病理学和治疗机制
- 批准号:
8109021 - 财政年份:2011
- 资助金额:
$ 31.94万 - 项目类别:
Mechanisms of Krabbe Disease Pathobiology and Therapy
克拉伯病病理学和治疗机制
- 批准号:
8448639 - 财政年份:2011
- 资助金额:
$ 31.94万 - 项目类别:
Mechanisms of Krabbe Disease Pathobiology and Therapy
克拉伯病病理学和治疗机制
- 批准号:
8643297 - 财政年份:2011
- 资助金额:
$ 31.94万 - 项目类别:
Development of S-Nitrosothiol-based Therapy for Alzheimer's Disease
基于 S-亚硝基硫醇的阿尔茨海默病疗法的开发
- 批准号:
8696815 - 财政年份:2011
- 资助金额:
$ 31.94万 - 项目类别:
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