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: 8384981
• 负责人: Michael Aschner
• 金额: $ 35.1万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8384981
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Affect; Alkaline Phosphatase; Alleles; Antioxidants; Astrocytes; Biochemical; Biological; Brain; Cell Survival; Cells; Data; Development; Event; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Screening; Genetic Transcription; Genomics; Genotype; Glutathione Disulfide; Heritability; Human; In Vitro; Inbred Mouse; Inbred Strains Mice; Injury; Isoprostanes; Light; Lipid Peroxidation; Mammalian Cell; Mediating; Metal exposure; Methylmercury Compounds; Mitochondria; Modeling; Modification; Molecular; Mouse Strains; Mus; Neonatal; Neuraxis; Neurobiology; Neurons; Neurotoxins; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Phenotype; Phosphorylation; Population; Predisposition; Production; Protein-Serine-Threonine Kinases; Protocols documentation; Quantitative Trait Loci; Rattus; Reactive Oxygen Species; Recombinants; Research; Resources; Response Elements; Role; Signal Pathway; Signal Transduction; Sulfhydryl Compounds; System; Testing; Thioredoxin; Toxic effect; Transcriptional Activation; Transfection; Transgenic Mice; Up-Regulation; Variant; biological systems; cell type; combat; developmental neurotoxicity; drinking water; gene environment interaction; in vivo; innovation; kinase inhibitor; nerve injury; neurobehavioral; neuroprotection; neurotoxic; neurotoxicity; novel; nuclear factor-erythroid 2; response; trait

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）是一种有效的神经毒素。我们假设在MEHG诱导的氧化应激的条件下，NRF2协调了对抗MEHG诱导的氧化损伤的细胞保护基因的上调，以及对NRF2功能的遗传和生化变化会增加MEHG MEHG的神经毒性。该假设的推论意味着（i）对MEHG诱导的遗传敏感性 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，（ii）NRF2上调的程度代表了对细胞特异性（星形胶质细胞与神经元）适应性反应的批评。 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.具体的目标1将确定MEHG在培养的鼠原代小脑星形胶质细胞和神经元中的暴露以及体内发育过程中是否诱导与NRF2转录激活相关的氧化应激。具体的目标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是否对于依赖MEHG的NRF2依赖性保护至关重要。具体目标3将测试NRF2遗传力在调节BXD RI小鼠菌株中MEHG敏感性中的作用。这些特定的目的有望划定MEHG神经保护的调节，对神经毒性机制的启示以及与这种金属暴露有关的敏感性。 公共卫生相关性：拟议的研究将提供有关（1）NRF2信号通路MEHG转录修饰的作用的新颖和创新信息，及其相关网络在调节神经发育毒性和神经保护方面的作用； （2）可能是MEHG与生物系统相互作用的广泛相互作用的功能领域； （3）易感性遗传特征在介导MEHG损伤的分子机制中的作用； （4）集成系统对MEHG的响应中物种内部和跨物种之间的基因环境相互作用。