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(申请人提供):脑创伤导致内皮和脑实质的炎症,统称为神经血管单位。虽然创伤性脑损伤(TBI)后神经元会因坏死而迅速死亡,但内皮细胞炎症的恶性循环会加剧损伤。在激活的内皮细胞中,过量的超氧化物与一氧化氮(NO)反应生成过氧亚硝酸根。脑外伤后高水平的过氧亚硝酸盐参与血脑屏障(BBB)渗漏、酶功能改变和神经行为障碍。它激活AMP激酶(AMPK),进而上调内皮型一氧化氮合酶(ENOS)的超氧化物生成活性,从而维持神经炎性继发性损伤的恶性循环。亚硝化试剂S-亚硝基谷胱甘肽(GSNO)能降低过氧亚硝酸根含量,抑制AMPK活性。它还可以恢复谷胱甘肽的水平,保护神经血管单位的完整性。因此,本研究将探讨GSNO治疗是否能通过亚硝酸化改善脑损伤后神经血管单位的神经炎性损伤。我们推测GSNO可阻断脑损伤后AMPK/eNOS/过氧亚硝酸盐的恶性循环,从而减轻神经血管损伤,帮助功能恢复。在具体目标1中,将使用药物(过氧亚硝酸盐清除剂GSNO和AMPK选择性抑制剂)作为治疗工具,在受控皮质撞击小鼠模型中剖析AMPK的调节和对脑损伤的改善。在特定目标2中,将使用AMPKα1/2基因敲除小鼠、AMPKα过表达转基因小鼠和野生型小鼠进一步检验和验证所阐明的机制。在具体目标3中,我们将确定GSNO介导的AMPK或其上游激酶LKB1的亚硝化是否与抑制eNOS异常活性和减少过氧亚硝酸盐的形成有关。互补的药理学和遗传学方法将决定AMPK在脑损伤中的作用。与传统的NO供体不同,GSNO是一种无毒的内源性NO调节剂和亚硝化试剂。了解S-亚硝化机制和独特的AMPK/eNOS/过氧亚硝酸盐通路可能为神经炎性脑损伤的治疗提供新的策略,不仅针对其神经元后果,而且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)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes
AMP 激活蛋白激酶对 1 型糖尿病免疫细胞调节的药理学靶向
- 批准号:
2867610 - 财政年份:2023
- 资助金额:
$ 31.94万 - 项目类别:
Studentship
Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease
建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂
- 批准号:
BB/W009633/1 - 财政年份:2022
- 资助金额:
$ 31.94万 - 项目类别:
Fellowship
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2021
- 资助金额:
$ 31.94万 - 项目类别:
Postdoctoral Fellowships
Metabolic control of integrin membrane traffic by AMP-activated protein kinase controls cell migration.
AMP 激活的蛋白激酶对整合素膜运输的代谢控制控制着细胞迁移。
- 批准号:
459043 - 财政年份:2021
- 资助金额:
$ 31.94万 - 项目类别:
Studentship Programs
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2020
- 资助金额:
$ 31.94万 - 项目类别:
Postdoctoral Fellowships
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10561642 - 财政年份:2019
- 资助金额:
$ 31.94万 - 项目类别:
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2019
- 资助金额:
$ 31.94万 - 项目类别:
Postdoctoral Fellowships
Treating Diabetic Inflammation using AMP-Activated Protein Kinase Activators
使用 AMP 激活的蛋白激酶激活剂治疗糖尿病炎症
- 批准号:
2243045 - 财政年份:2019
- 资助金额:
$ 31.94万 - 项目类别:
Studentship
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10359032 - 财政年份:2019
- 资助金额:
$ 31.94万 - 项目类别:
Investigating the therapeutic potential of AMP-activated protein kinase in myotonic dystrophy type 1
研究 AMP 激活蛋白激酶在 1 型强直性肌营养不良中的治疗潜力
- 批准号:
428988 - 财政年份:2019
- 资助金额:
$ 31.94万 - 项目类别:
Studentship Programs