Genetic Modulation of MeHg-Induced Oxidative Stress in the Developing Brain
发育中大脑中甲基汞诱导的氧化应激的基因调节
基本信息
- 批准号:8384981
- 负责人:
- 金额:$ 35.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-03 至 2017-03-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAddressAffectAlkaline PhosphataseAllelesAntioxidantsAstrocytesBiochemicalBiologicalBrainCell SurvivalCellsDataDevelopmentEventGenerationsGenesGeneticGenetic Predisposition to DiseaseGenetic ScreeningGenetic TranscriptionGenomicsGenotypeGlutathione DisulfideHeritabilityHumanIn VitroInbred MouseInbred Strains MiceInjuryIsoprostanesLightLipid PeroxidationMammalian CellMediatingMetal exposureMethylmercury CompoundsMitochondriaModelingModificationMolecularMouse StrainsMusNeonatalNeuraxisNeurobiologyNeuronsNeurotoxinsOutcomeOxidation-ReductionOxidative StressPathway interactionsPhenotypePhosphorylationPopulationPredispositionProductionProtein-Serine-Threonine KinasesProtocols documentationQuantitative Trait LociRattusReactive Oxygen SpeciesRecombinantsResearchResourcesResponse ElementsRoleSignal PathwaySignal TransductionSulfhydryl CompoundsSystemTestingThioredoxinToxic effectTranscriptional ActivationTransfectionTransgenic MiceUp-RegulationVariantbiological systemscell typecombatdevelopmental neurotoxicitydrinking watergene environment interactionin vivoinnovationkinase inhibitornerve injuryneurobehavioralneuroprotectionneurotoxicneurotoxicitynovelnuclear factor-erythroid 2responsetrait
项目摘要
DESCRIPTION (provided by applicant): Methylmercury (MeHg) is a potent neurotoxin. We hypothesize that under conditions of MeHg-induced oxidative stress, Nrf2 coordinates the upregulation of cytoprotective genes that combat MeHg- induced oxidative injury, and that genetic and biochemical changes that negatively impact upon Nrf2 function increase MeHg's neurotoxicity. Corollaries of this hypothesis imply (i) that genetic susceptibility to MeHg-induced
neurotoxicity correlates with Nrf2 expression levels and activation of downstream genes associated with antioxidant activity, and (ii) the degree of Nrf2 upregulation represents a critica determinant of cell-specific (astrocytes vs. neurons) adaptive responses to MeHg. The approach to testing these hypotheses includes biochemical and molecular characterization of Nrf2 signaling both in vivo and in vitro (primary astrocytes and neurons), and genetic correlates of neurobiological phenotypes (biochemical, morphological and neurobehavioral endpoints), taking full advantage of the unique BXD recombinant inbred (RI) mice. Specific Aim 1 will determine if MeHg exposure in cultured murine primary cerebellar astrocytes and neurons, and during development in vivo induces oxidative stress that correlates with Nrf2 transcriptional activation. Specific Aim 2 will evaluate whether the phosphatidylinositol 3-kinase (PI3K)-serine/threonine protein kinase Akt-mediated cell survival pathway is essential for Nrf2-dependent protection against MeHg. Specific Aim 3 will test the role of Nrf2 heritability in modulating MeHg susceptibility in BXD RI mouse strains. These specific aims hold the promise of delineating common initiator signals for the modulation of MeHg neuroprotection, shedding light on neurotoxic mechanisms and susceptibility associated with exposure to this metal.
PUBLIC HEALTH RELEVANCE: The proposed studies will provide novel and innovative information on (1) the role of transcriptional modifications by MeHg of the Nrf2 signaling pathway and its associated networks in modulating neurodevelopmental toxicity and neuroprotection; (2) functional domains that may underlie broad points of interaction of MeHg with biological systems; (3) the role of genetic traits of susceptibility in mediating molecular mechanisms of MeHg injury; and (4) gene-environment interactions within and across species in the integrated systems response to MeHg.
描述(由申请人提供):甲基汞(MeHg)是一种强效神经毒素。我们假设在甲基汞诱导的氧化应激条件下,Nrf2 协调细胞保护基因的上调,以对抗甲基汞诱导的氧化损伤,并且对 Nrf2 功能产生负面影响的遗传和生化变化会增加甲基汞的神经毒性。这一假设的推论意味着 (i) 对甲基汞诱发的遗传易感性
神经毒性与 Nrf2 表达水平和与抗氧化活性相关的下游基因的激活相关,并且 (ii) Nrf2 上调程度代表细胞特异性(星形胶质细胞与神经元)对 MeHg 适应性反应的关键决定因素。测试这些假设的方法包括体内和体外 Nrf2 信号传导(原代星形胶质细胞和神经元)的生化和分子表征,以及神经生物学表型(生化、形态学和神经行为终点)的遗传相关性,充分利用独特的 BXD 重组近交(RI)小鼠。具体目标 1 将确定培养的小鼠原代小脑星形胶质细胞和神经元中以及体内发育过程中的 MeHg 暴露是否会诱导与 Nrf2 转录激活相关的氧化应激。具体目标 2 将评估磷脂酰肌醇 3 激酶 (PI3K)-丝氨酸/苏氨酸蛋白激酶 Akt 介导的细胞存活途径对于 Nrf2 依赖性的 MeHg 保护是否至关重要。具体目标 3 将测试 Nrf2 遗传力在调节 BXD RI 小鼠品系的甲基汞敏感性中的作用。这些具体目标有望描述甲基汞神经保护调节的常见引发信号,揭示与接触这种金属相关的神经毒性机制和敏感性。
公共健康相关性:拟议的研究将提供以下方面的新颖和创新信息:(1) MeHg 对 Nrf2 信号通路及其相关网络的转录修饰在调节神经发育毒性和神经保护中的作用; (2) 可能是甲基汞与生物系统广泛相互作用点基础的功能域; (3)易感性遗传特征在介导甲基汞损伤分子机制中的作用; (4) 在甲基汞综合系统响应中,物种内部和物种之间的基因-环境相互作用。
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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Michael Aschner其他文献
Michael Aschner的其他文献
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{{ truncateString('Michael Aschner', 18)}}的其他基金
Genetic Susceptibility to Manganese Neurotoxicity
对锰神经毒性的遗传易感性
- 批准号:
9198920 - 财政年份:2016
- 资助金额:
$ 35.1万 - 项目类别:
Genetic Modulation of MeHg-Induced Oxidative Stress in the Developing Brain
发育中大脑中甲基汞诱导的氧化应激的基因调节
- 批准号:
8523412 - 财政年份:2012
- 资助金额:
$ 35.1万 - 项目类别:
Genetic Modulation of MeHg-Induced Oxidative Stress in the Developing Brain
发育中大脑中甲基汞诱导的氧化应激的基因调节
- 批准号:
9038365 - 财政年份:2012
- 资助金额:
$ 35.1万 - 项目类别:
Genetic Modulation of MeHg-Induced Oxidative Stress in the Developing Brain
发育中大脑中甲基汞诱导的氧化应激的基因调节
- 批准号:
8829856 - 财政年份:2012
- 资助金额:
$ 35.1万 - 项目类别:
Genetic Modulation of MeHg-Induced Oxidative Stress in the Developing Brain
发育中大脑中甲基汞诱导的氧化应激的基因调节
- 批准号:
9187666 - 财政年份:2012
- 资助金额:
$ 35.1万 - 项目类别:
Genetic Modulation of MeHg-Induced Oxidative Stress in the Developing Brain
发育中大脑中甲基汞诱导的氧化应激的基因调节
- 批准号:
8764000 - 财政年份:2012
- 资助金额:
$ 35.1万 - 项目类别:
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