DNA Repair and Replication in Oxidant Lung Injury

氧化性肺损伤中的 DNA 修复和复制

• 批准号: 6924577
• 负责人: Michael A O'Reilly
• 金额: $ 35.44万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6924577
• 关键词: Bax gene /protein; DNA damage; DNA repair; apoptosis; cell line; cytoprotection; hyperoxia; laboratory mouse; lung injury; oncoprotein p21; oxidative stress; p53 gene /protein; phosphoester ligase

DESCRIPTION (provided by applicant): The beneficial effects of supplemental oxygen to reduce tissue hypoxia in patients suffering from respiratory distress are well known. Unfortunately, oxygen is reduced to cytotoxic reactive oxygen species that damage DNA, proteins and lipids resulting in cell injury, death and inflammation. DNA repair and replication occur during recovery in room air as injured and dead cells are replaced. Failure to appropriately repair and proliferate can lead to cell death, inflammation, fibrosis and chronic lung disease. Therefore, identifying molecules that regulate DNA repair and replication is important for improving clinical outcomes for patients treated with hyperoxia. Recent studies have shown that hyperoxia activates the DNA damage-dependent pathway involving the p53 tumor suppressor. P53 accumulates in cells with damaged DNA and increases the expression of the cyclin-dependent kinase inhibitor p21Cip1/WAF1 (hereafter p21) or the proapoptotic gene bax. Studies using p21-deficient mice and cell lines reveal that p21 inhibits proliferation, thereby reducing cell death, inflammation and mortality. Surprisingly, hyperoxia also inhibited the expression of the DNA repair protein AP-endonuclease when p21 was induced, but not when it was absent. APE is also redox factor (Ref)-1, which reduces oxidized forms of transcription factors, such as p53. This suggests that p21 protects cells from oxidant damage by preventing DNA repair commitment when DNA is being damaged and regulates p53-dependent transcription. The studies proposed in Aim 1 will determine whether p21-deficient cells have more DNA fragmentation during hyperoxia due to increased repair activity, Aim 2 will determine whether APE/Ref-1 regulates DNA repair and p53 activity, and Aim 3 will determine whether p53-dependent apoptosis promotes tissue repair in the absence of p21. A better understanding of how p21 protects cells from oxygen-induced damage has therapeutic value for treatment of lung injury caused by hyperoxia as well as other as other inhaled pollutants that produce oxidant free radicals.

描述(由申请人提供)：众所周知，补充氧气可以减少呼吸窘迫患者的组织缺氧。不幸的是，氧被还原为细胞毒性的活性氧物种，破坏DNA、蛋白质和脂质，导致细胞损伤、死亡和炎症。DNA修复和复制发生在室内空气中的恢复过程中，因为受伤和死亡的细胞被替换。如果没有适当的修复和增殖，可能会导致细胞死亡、炎症、纤维化和慢性肺部疾病。因此，识别调节DNA修复和复制的分子对于改善高氧治疗患者的临床结果非常重要。最近的研究表明，高氧激活了DNA损伤依赖的通路，涉及到P53抑癌基因。P53在DNA受损的细胞中积聚，并增加细胞周期蛋白依赖性激酶抑制因子p21Cip1/WAF1(以下简称p21)或促凋亡基因Bax的表达。使用p21缺陷小鼠和细胞系的研究表明，p21抑制增殖，从而减少细胞死亡、炎症和死亡率。令人惊讶的是，当p21被诱导时，高氧也抑制了DNA修复蛋白AP-内切酶的表达，但当它不存在时，高氧并不抑制DNA修复蛋白AP-内切酶的表达。APE也是氧化还原因子(Ref)-1，可减少氧化形式的转录因子，如P53。这表明当DNA损伤时，p21通过阻止DNA修复承诺和调节p53依赖的转录来保护细胞免受氧化损伤。目标1提出的研究将确定p21缺陷细胞在高氧时是否由于修复活性增加而有更多的DNA片段化，目标2将确定APE/Ref-1是否调节DNA修复和p53活性，目标3将确定在没有p21的情况下依赖于p53的细胞凋亡是否促进组织修复。更好地了解p21如何保护细胞免受氧诱导的损伤，对于治疗高氧引起的肺损伤以及其他产生氧化自由基的吸入污染物具有治疗价值。