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
• 负责人: Michael Aschner
• 金额: $ 7.85万
• 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 2013-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523412
• 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.

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MeHg诱导的氧化应激条件下，Nrf2协调抗MeHg诱导的氧化损伤的细胞保护基因的上调，并且对Nrf2功能产生负面影响的遗传和生化变化增加了MeHg的神经毒性。这一假设的推论表明：(1)对甲基汞的遗传易感性诱导