Novel Mechanisms of Microglial Neurotoxicity at Physiological Oxygen
生理氧下小胶质细胞神经毒性的新机制
基本信息
- 批准号:8739686
- 负责人:
- 金额:$ 33.24万
- 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:2013-09-30 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAntioxidantsBinding SitesBrainBypassCell Culture TechniquesCell DeathCellsChronicCoculture TechniquesComplexCysteineElectron Transport Complex IIIElectronsEngineeringEnzymesEstersExposure toGenus HippocampusGlutathioneGoalsImmuneImpairmentIn VitroIndividualInflammatory ResponseInjuryKnock-outLinkMeasurementMeasuresMediatingMicrogliaMitochondriaMitochondrial ProteinsModificationNQO1 geneNerve DegenerationNeurodegenerative DisordersNeuronal InjuryNeuronsNitric OxideOxygenPathway interactionsPeptidesPeroxonitritePharmaceutical PreparationsPhysiologicalProtein SReactionRelative (related person)ResearchResistanceRespirationResponse ElementsRestS-NitrosothiolsSuccinate DehydrogenaseSulfhydryl CompoundsSulforaphaneSuperoxidesTechnologyTestingTherapeuticTherapeutic InterventionTimeToxic effectTyrosineUbiquinoneanalogattenuationbrain cellcomplex IVcytokinedesignhuman NOS2A proteinidebenoneimprovedmitochondrial dysfunctionmutantnerve injuryneuroinflammationneuronal survivalneurotoxicitynitrationnovelnovel therapeuticsoverexpressionplanetary Atmospherepreventpublic health relevancerelating to nervous systemresearch studyrespiratorysuccess
项目摘要
DESCRIPTION (provided by applicant): Neuroinflammation occurs in both acute and chronic neurodegenerative disorders and contributes to neural injury. Microglial cells are activated in the
inflammatory response, releasing cytokines, nitric oxide (NO), and superoxide which target neighboring neurons. The overwhelming majority of studies investigating neurodegenerative disease mechanisms in vitro are conducted at atmospheric O2 despite the fact that this pO2 (21%, 160 mm Hg) far exceeds physiological brain pO2 (~3%, 23 mm Hg). We propose that pO2 fundamentally influences the mechanisms of neuronal injury and impacts the success of therapeutic strategies. We found that at 3% O2, NO-mediated inhibition of cortical neuron respiration is over 10-fold more potent than at atmospheric O2, and, in contrast to current dogma, occurs without inhibition of complex IV but with inhibition of complex II. This study will test the central hypothesis that at brain physiological O2, NO derived from microglial inducible nitric oxide synthase (iNOS) causes cortical neuron injury by S-nitrosylation-mediated inactivation of succinate dehydrogenase upstream of complex III rather than by NO or peroxynitrite-mediated inhibition of complex IV. Clinically safe idebenone, a short chain Coenzyme Q analogue which upon reduction by NQO1 enzyme can shuttle electrons from cytoplasmic NAD(P)H directly to complex III, will be tested for the ability to bypass an upstream respiratory impairment, rescue ATP levels, and improve neuronal survival at either 3% or 21% O2. We predict that drugs that induce the Nrf2/antioxidant response element pathway will potently synergize with idebenone by 1) upregulating NQO1 and by 2) increasing the pool of the endogenous antioxidant glutathione which can prevent cysteine S-nitrosothiol modifications. In aim 1 we will determine how pO2 influences the mechanism of neurotoxicity exerted by activated microglia. In aim 2 we will determine whether exogenous NO impairs mitochondrial function in cortical neurons at physiological (3%) O2 by reversible S-nitrosylation-mediated inhibition of succinate dehydrogenase (complex II). In aim 3 we will determine whether idebenone, when combined with an inducer of the Nrf2/antioxidant response element pathway, sulforaphane, can bypass NO-mediated respiratory inhibition and prevent microglial toxicity. We will for the first time perform neuronal respiration measurements at physiological 3% O2 using the Seahorse XF24 and also adapt this technology for examining neuronal respiratory impairments caused by co-cultured, activated microglia. Our long-term goals are to elucidate mitochondrial mechanisms of neural injury and identify new avenues for therapeutic intervention. Here, we will take important steps toward these goals by 1) determining how pO2 influences neuronal injury, with the potential for a paradigm-shifting change in the way in vitro neurodegenerative research is conducted, and by 2) providing proof-of-principle on whether bypass of respiratory inhibition is a viable strategy to reduce microglial neurotoxicity.
描述(由申请人提供):神经炎症发生在急性和慢性神经退行性疾病中,并导致神经损伤。小胶质细胞在大脑皮层中被激活,
炎症反应,释放细胞因子,一氧化氮(NO)和超氧化物,靶向邻近的神经元。绝大多数研究神经退行性疾病机制的体外研究都是在大气O2下进行的,尽管该pO 2(21%,160 mm Hg)远远超过生理脑pO 2(~ 3%,23 mm Hg)。我们认为pO 2从根本上影响神经元损伤的机制,并影响治疗策略的成功。我们发现,在3%O2,NO介导的抑制皮质神经元呼吸是超过10倍更有效的比在大气中O2,并在目前的教条相反,发生没有抑制复合物IV,但抑制复合物II。本研究将测试的中心假设,在脑生理O2,NO来自小胶质细胞诱导型一氧化氮合酶(iNOS)导致皮质神经元损伤的S-亚硝基化介导的复合物III的琥珀酸脱氢酶上游的失活,而不是NO或过氧亚硝酸盐介导的复合物IV的抑制。临床上安全的艾地苯醌是一种短链辅酶Q类似物,在被NQO 1酶还原后,可以将电子从细胞质NAD(P)H直接穿梭到复合物III,将测试艾地苯醌在3%或21% O2下绕过上游呼吸障碍、拯救ATP水平和改善神经元存活的能力。我们预测,诱导Nrf 2/抗氧化剂反应元件途径的药物将通过1)上调NQO 1和2)增加内源性抗氧化剂谷胱甘肽(可防止半胱氨酸S-亚硝基硫醇修饰)的库,与艾地苯醌有效协同作用。在目标1中,我们将确定pO 2如何影响激活的小胶质细胞产生神经毒性的机制。在目标2中,我们将确定是否外源性NO损害线粒体功能在皮层神经元在生理(3%)O2的可逆S-亚硝基化介导的抑制琥珀酸脱氢酶(复合物II)。在目标3中,我们将确定艾地苯醌与Nrf 2/抗氧化反应元件途径的诱导剂萝卜硫素组合时是否可以绕过NO介导的呼吸抑制并防止小胶质细胞毒性。我们将首次使用Seahorse XF 24在生理3% O2下进行神经元呼吸测量,并将该技术用于检查由共培养的活化小胶质细胞引起的神经元呼吸损伤。我们的长期目标是阐明神经损伤的线粒体机制,并确定治疗干预的新途径。在这里,我们将通过以下方式朝着这些目标迈出重要一步:1)确定pO 2如何影响神经元损伤,以及体外神经退行性研究方式的范式转变可能性; 2)提供关于呼吸抑制旁路是否是减少小胶质细胞神经毒性的可行策略的原理证明。
项目成果
期刊论文数量(0)
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BRIAN M POLSTER其他文献
BRIAN M POLSTER的其他文献
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{{ truncateString('BRIAN M POLSTER', 18)}}的其他基金
Targeting TREM2 AD/ADRD risk and immunometabolism in human microglia
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Targeting mitochondrial Complex I in neonatal hypoxia-ischemia
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Targeting mitochondrial Complex I in neonatal hypoxia-ischemia
靶向线粒体复合物 I 在新生儿缺氧缺血中的作用
- 批准号:
10560643 - 财政年份:2022
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$ 33.24万 - 项目类别:
Reprogramming proinflammatory microglia by restoring mitochondrial function
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- 批准号:
10201784 - 财政年份:2020
- 资助金额:
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Reprogramming proinflammatory microglia by restoring mitochondrial function
通过恢复线粒体功能重新编程促炎性小胶质细胞
- 批准号:
10661552 - 财政年份:2020
- 资助金额:
$ 33.24万 - 项目类别:
Reprogramming proinflammatory microglia by restoring mitochondrial function
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- 批准号:
10447013 - 财政年份:2020
- 资助金额:
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Mitochondrial Structural and Functional Remodeling in Microglial Activation
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- 批准号:
9093229 - 财政年份:2016
- 资助金额:
$ 33.24万 - 项目类别:
Novel Mechanisms of Microglial Neurotoxicity at Physiological Oxygen
生理氧下小胶质细胞神经毒性的新机制
- 批准号:
8612571 - 财政年份:2013
- 资助金额:
$ 33.24万 - 项目类别:
Proteolytic Fragments and Mitochondrial Dysfunction in TBI
TBI 中的蛋白水解片段和线粒体功能障碍
- 批准号:
7631880 - 财政年份:2009
- 资助金额:
$ 33.24万 - 项目类别:
Proteolytic Fragments and Mitochondrial Dysfunction in TBI
TBI 中的蛋白水解片段和线粒体功能障碍
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8217233 - 财政年份:2009
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