• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >From Neural Stem Cells to Children: Secreted Phosphoprotein 1 in Lead Neurotoxicity.
【24h】

From Neural Stem Cells to Children: Secreted Phosphoprotein 1 in Lead Neurotoxicity.

机译：从神经干细胞到儿童：铅神经毒性中分泌的磷蛋白1。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Lead (Pb) exposure in the earliest stages of neurodevelopment leads to lasting deficits in cognitive function and behavior. Neural stem cells (NSCs) are multipotent stem cells and the first cells of the central nervous system, but little is known of their molecular response to Pb exposure. We exposed human NSCs to 1microM Pb for 24 hours and performed RNA sequencing. 16 of 19 differentially expressed transcripts are upregulated, and of these 10 are known targets of NRF2, the master transcriptional regulator of the cellular antioxidant response. One of the top Pb-induced genes, Secreted Phosphoprotein 1 (SPP1), was not a previously known NRF2 target. We show SPP1 is induced following activation of NRF2 by other known activators and by knockdown of its negative regulator KEAP1. In addition, the induction of SPP1 by Pb was attenuated after siRNA-mediated knockdown of NRF2. We identified a putative Antioxidant Response Element in the SPP1 promoter and confirmed its function by Chromatin immunoprecipitation (ChIP) of NRF2. To further investigate the role of SPP1 in neurodevelopment, we examined SPP1 single nucleotide polymorphisms (SNPs) in a longitudinal birth cohort of infants profiled at 24 months for the mental and psychomotor development indices (MDI and PDI, respectively) of the Bayley Scales of Infant Development. Sixteen single nucleotide polymorphisms (SNPs) in and near SPP1 were tested for main effect and effect modification. For main effect on MDI, eight SNPs are associated at p<0.05, but none pass multiple testing correction. In PDI analyses, SNP rs4693923 shows statistically significant effect modification on the PDI response to second trimester Pb exposure. A-allele carriers of this SNP show a positive correlation between Pb exposure and PDI, which is not seen among GG homozygotes. Together our studies show SPP1 is a novel target of NRF2 and suggest a critical role for SPP1 in modulating prenatal Pb neurotoxicity.
机译：在神经发育的最早阶段，铅（Pb）暴露会导致认知功能和行为的持久缺陷。神经干细胞（NSCs）是多能干细胞，是中枢神经系统的第一个细胞，但对其对Pb暴露的分子反应知之甚少。我们将人类NSC暴露于1microM Pb中24小时，然后进行RNA测序。 19种差异表达的转录本中有16种被上调，而这10种是NRF2（细胞抗氧化剂反应的主要转录调节因子）的已知靶标。铅诱导的最高基因之一是分泌性磷蛋白1（SPP1），不是以前已知的NRF2靶标。我们显示SPP1是由其他已知的激活剂和其负极调节剂KEAP1的敲除诱导NRF2激活后诱导的。另外，在siRNA介导的NRF2敲低后，Pb对SPP1的诱导减弱。我们在SPP1启动子中鉴定出假定的抗氧化反应元件，并通过NRF2的染色质免疫沉淀（ChIP）确认了其功能。为了进一步研究SPP1在神经发育中的作用，我们检查了24个月婴儿的纵向和出生队列中SPP1单核苷酸多态性（SNPs）的Bayley婴儿智力和精神运动发育指数（分别为MDI和PDI）。发展。测试了SPP1及其附近的16个单核苷酸多态性（SNP）的主要作用和作用修饰。对于MDI的主要影响，八个SNP在p <0.05时关联，但没有一个通过多次测试校正。在PDI分析中，SNP rs4693923显示对妊娠中期Pb暴露的PDI响应具有统计学上显着的影响修饰。该SNP的A等位基因携带者在Pb暴露和PDI之间显示正相关，而在GG纯合子中则没有。我们的研究在一起表明，SPP1是NRF2的新型靶标，并表明SPP1在调节产前Pb神经毒性中起关键作用。

著录项

  • 作者

    Wagner, Peter John.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Toxicology.;Developmental biology.;Genetics.;Molecular biology.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 80 p.
  • 总页数 80
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号