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
• 负责人: Michael Aschner
• 金额: $ 37.58万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 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 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038365
• 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; Glycogen Synthase Kinases; 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; Proteins; Protocols documentation; Quantitative Trait Loci; Rattus; Reactive Oxygen Species; Recombinants; Research; Resources; Response Elements; Role; Signal Pathway; Signal Transduction; Sulfhydryl Compounds; System; TXN gene; Testing; 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，在甲基汞诱导的氧化应激条件下，Nrf 2协调细胞保护基因的上调，对抗甲基汞诱导的氧化损伤，以及对Nrf 2功能产生负面影响的遗传和生化变化增加甲基汞的神经毒性。这一假设的推论意味着（i）遗传易感性的甲基汞诱导 神经毒性与Nrf 2的表达水平和下游基因的激活与抗氧化活性相关，和（ii）Nrf 2上调的程度代表了细胞特异性（星形胶质细胞与神经元）适应性反应甲基汞的关键决定因素。检验这些假设的方法包括体内和体外Nrf 2信号传导的生化和分子表征（原代星形胶质细胞和神经元），以及神经生物学表型的遗传相关性（生物化学，形态学和神经行为终点），充分利用独特的BXD重组近交系（RI）小鼠。具体目标1将确定甲基汞暴露在培养的小鼠原代小脑星形胶质细胞和神经元中，以及在体内发育过程中是否会诱导与Nrf 2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（PI 3 K）-丝氨酸/苏氨酸蛋白激酶Akt介导的细胞存活途径是否对Nrf 2依赖性保护甲基汞至关重要。具体目标3将测试Nrf 2遗传性在调节BXD RI小鼠品系的甲基汞易感性中的作用。这些具体的目标持有的承诺划定共同的启动信号的调制甲基汞神经保护，揭示神经毒性机制和易感性与接触这种金属。

项目成果

Bladder cancer in crack testers applying azo dye-based sprays to metal bodies.

将偶氮染料喷雾剂应用于金属体的裂纹测试仪中的膀胱癌。

• DOI: 10.1080/15287394.2012.675309
• 发表时间: 2012
• 期刊: Journal of toxicology and environmental health. Part A
• 作者: Golka,Klaus;Kopps,Silke;Prager,Hans-Martin;Mende,Stephanv;Thiel,Ralf;Jungmann,Olaf;Zumbe,Jürgen;Bolt,HermannM;Blaszkewicz,Meinolf;Hengstler,JanG;Selinski,Silvia
• 通讯作者: Selinski,Silvia

Matairesinol Nanoparticles Restore Chemosensitivity and Suppress Colorectal Cancer Progression in Preclinical Models: Role of Lipid Metabolism Reprogramming.

Matairesinol 纳米颗粒在临床前模型中恢复化学敏感性并抑制结直肠癌进展：脂质代谢重编程的作用。

• DOI: 10.1021/acs.nanolett.3c00035
• 发表时间: 2023
• 期刊: Nano letters
• 影响因子: 10.8
• 作者: Wu,Shenshen;Wang,Jiajia;Fu,Zan;Familiari,Giuseppe;Relucenti,Michela;Aschner,Michael;Li,Xiaobo;Chen,Hanqing;Chen,Rui
• 通讯作者: Chen,Rui

Mercury in Our Food.

我们的食物中含有汞。

• DOI: 10.1021/acs.chemrestox.9b00126
• 发表时间: 2019
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Nogara,PabloA;Farina,Marcelo;Aschner,Michael;Rocha,JoaoBT
• 通讯作者: Rocha,JoaoBT

Comparison of the neurotoxicity associated with cobalt nanoparticles and cobalt chloride in Wistar rats.

比较钴纳米颗粒和氯化钴对 Wistar 大鼠的神经毒性。

• DOI: 10.1016/j.taap.2019.03.003
• 发表时间: 2019
• 期刊: Toxicology and Applied Pharmacology
• 影响因子: 3.8
• 作者: Zheng Fuli;Luo Zhousong;Zheng Chunyan;Li Jing;Zeng Jingwen;Yang Hongyu;Chen Jinfa;Jin Yanqiao;Aschner Michael;Wu Siying;Zhang Qunwei;Li Huangyuan
• 通讯作者: Li Huangyuan

Early Expression of Neuronal Dopaminergic Markers in a Parkinson's Disease Model in Rats Implanted with Enteric Stem Cells (ENSCs).

植入肠干细胞 (ENSC) 的大鼠帕金森病模型中神经元多巴胺能标记的早期表达。

• DOI: 10.2174/1871527319666200417123948
• 发表时间: 2020
• 期刊: CNS & neurological disorders drug targets
• 作者: Parra-Cid,Carmen;Orozco-Castillo,Eduardo;García-López,Julieta;Contreras-Figueroa,Elena;Ramos-Languren,LauraE;Ibarra,Clemente;Carreón-Rodríguez,Alfonso;Aschner,Michael;Königsberg,Mina;Santamaría,Abel
• 通讯作者: Santamaría,Abel