Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
基本信息
- 批准号:8113936
- 负责人:
- 金额:$ 30.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-08-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdipocytesAgeAge-associated memory impairmentAgingAlzheimer&aposs DiseaseAmygdaloid structureAnimalsAnti-Inflammatory AgentsAnti-inflammatoryAstrocytesAttentionBehaviorBehavioralBiologicalBiologyBrainBrain regionCanis familiarisCell Culture TechniquesCellsChronicChronic DiseaseCognitiveCognitive deficitsCollaborationsComplexDeliriumDevelopmentDiseaseElderlyElectron Spin Resonance SpectroscopyElectrophysiology (science)EmotionalEtiologyEventFluorescenceFunctional disorderGeneticGenetic VariationHealthHippocampus (Brain)HormonesHumanHydrogen PeroxideImageImmunotherapyImpaired cognitionInflammationInflammation MediatorsInflammatoryInterleukin-10Interleukin-6InterneuronsInterventionIon ChannelLearningLifeLinkMediatingMediator of activation proteinMemoryMicrogliaModelingModificationMolecularMultienzyme ComplexesMusMuscleNADPH OxidaseNeuraxisNeuronsNeurotransmitter ReceptorNuclearOperative Surgical ProceduresOutcomeOutcome MeasureOxidantsOxidation-ReductionParvalbuminsPathway interactionsPerformancePharmaceutical PreparationsPhenotypePhysiologicalPlasmaPrimatesProcessProductionProtein IsoformsReactive Oxygen SpeciesReportingRiskRodentRoleSeriesSignal TransductionSliceSocietiesSourceStressSuperoxidesSynapsesTNF geneTechniquesTestingTreatment EfficacyWild Type Mouseage relatedagedaging brainbehavior testcell typecognitive changecognitive functionconditioned fearcytokinedesigndisabilityfluorescence imagingfrailtyhuman CYBA proteinin vivoinflammatory markerinformation processinginhibitory neuroninsightmemory encodingmiddle agemortalitymouse modelmuscle formmuscle strengthneural circuitneuron lossneutrophilpreventprotein expressionpublic health relevancesenescencestressorsuperoxide-generating NADPH oxidasetranscription factor
项目摘要
DESCRIPTION (provided by applicant): Increasing evidence indicates that adverse health outcomes in older adults are strongly associated with the development of a state of chronic, mild inflammation. In humans, circulating markers of inflammation, including the inflammatory cytokine interleukin-6 (IL-6), are associated with, or predict, enhanced risk of frailty, loss of muscle mass and strength, disability, and early mortality, as well as acute and chronic cognitive decline, development of Alzheimer's disease, and drug- and stress-induced delirium. IL-6 activates a host of inflammatory actions through classical Jak/STAT pathway, but we recently found that IL-6, acting through non-cannonical activation of the transcription factor, NFkB, induces neuronal expression and activation of NADPH oxidase (Nox2), a multimeric enzyme complex first described as the respiratory burst oxidase in neutrophils. Nox2 is designed to produce large amounts of reactive oxygen species (ROS), primarily superoxide anion. We have further shown that Nox2 is induced and activated in neurons in the aging brain, and that Nox2 is in fact the major source of neuronal and synaptic superoxide production in aged mice. Inflammatory induction of Nox2 led to a superoxide-dependent loss of subsets of inhibitory interneurons in hippocampus, cortex, and amygdala. Loss of these neurons is observed in rodents, dogs, and primates, and has been proposed to underlie cognitive deficits across cognitive domains. We will test the hypothesis that age-related increase in IL-6, potentially mediated by the inflammatory cytokine TNFa or loss of the anti-inflammatory cytokine IL-10, induces neuronal Nox2 expression and that Nox2, in turn, results in persistent deficits in inhibitory neural circuits required for learning, attention, and memory encoding. Aged wild-type mice, and aged mice with modifications (either genetic or pharmacologic) which modify IL-6 expression, signaling, or specific downstream targets, will be used to test our hypothesis. A variety of techniques, including live animal fluorescence imaging of Nox2 activity, EPR, confocal imaging, immuno-fluorescence, electrophysiology and behavioral testing of brain region-specific function (e.g. spatial learning, a hippocampal CA3-dependent process) will be used to test each link in our hypothesized sequence. Finally, a series of interventional studies with drugs and immunotherapies which modulate IL-6, or the proposed sequence of events, will be carried out to determine whether age-related cognitive deficits in the mice are ameliorated, and to further test our hypothetical sequence. Importance to Human Health: Changes in cognitive function are an important health concern for older adults, and for society. The link between inflammatory pathway activation and aging in the brain remains to be fully defined. The studies proposed here are designed to explore one pathway which may link inflammatory pathways and age-related cognitive deficits, with the potential to provide additional insights into important and possibly reversible biological and neural circuitry changes in the aging brain.
PUBLIC HEALTH RELEVANCE: Older adults are more vulnerable to the development of adverse cognitive outcomes, including decline in cognitive function and the development of delirium, after acute illness, surgery, and other stressors. The exact etiology and molecular mechanisms are not known, but recent studies suggest a role for the pro- inflammatory cytokine interleukin-6 (IL-6) in many aging-related disorders, including cognitive vulnerability. Our project seeks to determine the mechanisms which underlie the association between systemic inflammation, IL-6, and cognitive vulnerability, and to try to determine whether interventions which target IL-6 or downstream pathways might prevent age-related cognitive decline.
描述(由申请人提供):越来越多的证据表明,老年人的不良健康后果与慢性轻度炎症状态的发展密切相关。在人类中,循环中的炎症标志物,包括炎症细胞因子白介素6(IL-6),与虚弱、肌肉质量和力量丧失、残疾和早期死亡的风险增加,以及急性和慢性认知能力下降、阿尔茨海默病的发展以及药物和应激诱导的精神错乱有关,或可预测。IL-6通过经典的JAK/STAT途径激活一系列炎症活动,但我们最近发现,IL-6通过非常规激活转录因子NFkB,诱导神经元表达和激活NADPH氧化酶(NOX2),这是一种最先被描述为中性粒细胞呼吸爆发氧化酶的多聚体酶复合体。NOX2的设计目的是产生大量的活性氧物种(ROS),主要是超氧阴离子。我们进一步证明,NOX2在衰老的大脑中的神经元中被诱导和激活,并且NOX2实际上是衰老小鼠神经元和突触产生超氧化物的主要来源。NOX2的炎症诱导导致海马区、皮质和杏仁核中的抑制性中间神经元亚群的超氧化物依赖丢失。在啮齿动物、狗和灵长类动物中观察到这些神经元的丢失,并被认为是认知领域认知缺陷的基础。我们将测试一种假设,即与年龄相关的IL-6的增加,潜在地由炎症细胞因子TNFa或抗炎细胞因子IL-10的缺失介导,诱导神经元NOX2的表达,而NOX2反过来导致学习、注意力和记忆编码所需的抑制性神经回路的持续缺陷。衰老的野生型小鼠,以及修改了IL-6表达、信号或特定下游靶点的老年小鼠(无论是遗传上的还是药物上的),都将被用来检验我们的假设。各种技术,包括NOX2活性的实时动物荧光成像、EPR、共聚焦成像、免疫荧光、电生理学和大脑区域特定功能的行为测试(例如,空间学习,海马区CA3依赖的过程)将被用来测试我们假设的序列中的每个环节。最后,将进行一系列药物和免疫疗法的干预性研究,以调节IL-6或拟议的事件序列,以确定小鼠与年龄相关的认知缺陷是否得到改善,并进一步检验我们的假设序列。对人类健康的重要性:认知功能的变化是老年人和社会关注的一个重要健康问题。炎症途径激活与大脑衰老之间的联系仍未完全明确。这里提出的研究旨在探索一条可能将炎症途径和年龄相关的认知障碍联系起来的途径,并有可能为衰老大脑中重要的、可能可逆的生物和神经回路变化提供更多的见解。
与公共卫生相关:老年人更容易在急性疾病、手术和其他应激源后出现不良认知结果,包括认知功能下降和发展为精神错乱。确切的病因和分子机制尚不清楚,但最近的研究表明,促炎细胞因子白介素6(IL-6)在许多与衰老相关的疾病中发挥了作用,包括认知障碍。我们的项目试图确定全身炎症、IL-6和认知脆弱性之间联系的基础机制,并试图确定针对IL-6或下游通路的干预是否可以防止与年龄相关的认知能力下降。
项目成果
期刊论文数量(0)
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Laura L Dugan其他文献
Mitochondrial Uncoupling Proteins in the Central Nervous System Recommended Citation
中枢神经系统中的线粒体解偶联蛋白推荐引文
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Jeong Sook;Kim;Laura L Dugan;Dugan;Laura L - 通讯作者:
Laura L
Laura L Dugan的其他文献
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{{ truncateString('Laura L Dugan', 18)}}的其他基金
Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
- 批准号:
10514598 - 财政年份:2019
- 资助金额:
$ 30.44万 - 项目类别:
Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
- 批准号:
9665155 - 财政年份:2019
- 资助金额:
$ 30.44万 - 项目类别:
Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
- 批准号:
10043824 - 财政年份:2019
- 资助金额:
$ 30.44万 - 项目类别:
Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
- 批准号:
10292955 - 财政年份:2019
- 资助金额:
$ 30.44万 - 项目类别:
Inflammatory Mechanisms Underlie Lysosome Failure in the Aging Brain
炎症机制是衰老大脑中溶酶体衰竭的基础
- 批准号:
10159817 - 财政年份:2018
- 资助金额:
$ 30.44万 - 项目类别:
Inflammatory Mechanisms Underlie Lysosome Failure in the Aging Brain
炎症机制是衰老大脑中溶酶体衰竭的基础
- 批准号:
10406349 - 财政年份:2018
- 资助金额:
$ 30.44万 - 项目类别:
Inflammatory Mechanisms Underlie Lysosome Failure in the Aging Brain
炎症机制是衰老大脑中溶酶体衰竭的基础
- 批准号:
9923516 - 财政年份:2018
- 资助金额:
$ 30.44万 - 项目类别:
Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
- 批准号:
9293672 - 财政年份:2010
- 资助金额:
$ 30.44万 - 项目类别:
Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
- 批准号:
8292022 - 财政年份:2010
- 资助金额:
$ 30.44万 - 项目类别:
Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
- 批准号:
8705765 - 财政年份:2010
- 资助金额:
$ 30.44万 - 项目类别:
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