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首页> 外文学位 >The Nrf2/ARE pathway influences intrinsic radiosensitivity and is activated by exposure to ionizing radiation.
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The Nrf2/ARE pathway influences intrinsic radiosensitivity and is activated by exposure to ionizing radiation.

机译：Nrf2 / ARE途径影响固有的放射敏感性，并通过暴露于电离辐射而被激活。

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摘要

This dissertation explores the radiomodulatory affects of the Nrf2/Antioxidant Response Element (Nrf2/ARE) pathway. Exposure to ionizing radiation produces a large amount of reactive oxygen species (ROS) that are a major source of DNA damage. Activation of the Nrf2/ARE pathway increases production of antioxidant enzymes that might be expected to be cytoprotective. However, initial studies with several Nrf2-inducing agents found treatment prior to ionizing radiation failed to protect lymphocytes against radiation-induced apoptosis and several other cell types against cell death in longer term, clonogenic assays.;Nrf2-deficient mouse models were then used to test the impact of the Nrf2/ARE pathway on intrinsic cellular radiosensitivity. Mouse embryo fibroblasts with loss of Nrf2 had decreased expression of heme oxygenase 1 (HO-1) protein expression and glutathione activity, as expected, and after exposure to ionizing radiation dramatically increased ROS formation relative to wild type cells. Although no differences in initial DNA double strand breaks was observed, Nrf2 deficient cells were more radiosensitive under both aerobic and hypoxic conditions. Furthermore, Nrf2-deficient mice were sensitive to whole body irradiation with doses that were sublethal for wild type and heterozygous mice, supporting a radioprotective role of the Nrf2/ARE pathway.;Studies finally focused on the ability of repeated damage to activate the Nrf2/ARE pathway over time, using a gene reporter system. No change was observed 1 to 24 hours after single dose radiation exposure, but by day 5 there was a dose-dependent increase in ARE-reporter activity above 2Gy. This correlated with expression of HO-1 in several cell lines. Similar results were obtained with five daily fractions of I to 4Gy given to cells in vitro and in spleens from irradiated mice. These data suggest that ARE-activation of cytoprotective enzymes is due to persistent oxidative stress after ionizing radiation exposure.;These studies are the first to report on the impact of the Nrf2/ARE pathway on intrinsic cellular radiosensitivity and activation by ionizing radiation.
机译：本文探讨了Nrf2 /抗氧化反应元件（Nrf2 / ARE）途径的辐射调节作用。暴露于电离辐射中会产生大量的活性氧（ROS），这是DNA损伤的主要来源。 Nrf2 / ARE途径的激活增加了抗氧化酶的产生，这种抗氧化酶可能具有细胞保护作用。但是，对几种Nrf2诱导剂的初步研究发现，在长期的克隆形成试验中，电离辐射之前的治疗无法保护淋巴细胞免受辐射诱导的细胞凋亡以及其他几种细胞类型的细胞死亡。;然后使用缺乏Nrf2的小鼠模型测试Nrf2 / ARE途径对固有细胞放射敏感性的影响。如预期的那样，丢失Nrf2的小鼠胚胎成纤维细胞具有降低的血红素加氧酶1（HO-1）蛋白表达和谷胱甘肽活性，并且在暴露于电离辐射后，相对于野生型细胞而言，ROS形成显着增加。尽管未观察到初始DNA双链断裂的差异，但缺氧和缺氧条件下Nrf2缺陷细胞对放射敏感性更高。此外，Nrf2缺陷小鼠对野生型和杂合小鼠亚致死剂量的全身辐射敏感，支持Nrf2 / ARE途径的辐射防护作用。研究最终集中于反复损伤激活Nrf2 /的能力。使用基因报告系统，随着时间的推移获得ARE途径。单剂量辐射暴露后1至24小时未观察到变化，但到第5天，高于2Gy的ARE报告基因活性呈剂量依赖性增加。这与HO-1在几种细胞系中的表达相关。在体外和辐照小鼠的脾脏中，每天给予I至4Gy的5个每日级分，可获得类似的结果。这些数据表明，细胞保护酶的ARE活化是由于电离辐射暴露后持续的氧化应激引起的。这些研究是第一个报道Nrf2 / ARE途径对内在细胞放射敏感性和电离辐射活化的影响的研究。

著录项

  • 作者

    McDonald, John Tyson.;

  • 作者单位

    University of California, Los Angeles.;

  • 授予单位 University of California, Los Angeles.;
  • 学科 Biology Molecular.;Physics Radiation.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 101 p.
  • 总页数 101
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:30

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