Pathways for oxidative damage of DNA by phagocytes

吞噬细胞氧化损伤 DNA 的途径

• 批准号: 6763125
• 负责人: JAY W HEINECKE
• 金额: $ 30.32万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6763125
• 关键词: DNA damage; chemical carcinogenesis; electrospray ionization mass spectrometry; emphysema; eosinophil; eosinophilic granuloma; gas chromatography mass spectrometry; high performance liquid chromatography; infection related neoplasm /cancer; inflammation; laboratory mouse; lung; lung neoplasms; myeloperoxidase; nitrogen; nuclear magnetic resonance spectroscopy; nucleobase; oxidative stress; phagocytes; schistosomiasis; smoking; tobacco abuse

DESCRIPTION (Provided by Applicant): Oxidants generated by activated white blood cells are critical to host defenses against microorganisms. However, reactive species damage proteins and lipids and therefore might also damage host tissue. Moreover, they also oxidize nucleic acids and therefore could compromise the integrity of the genome. Such damage might account for the association between chronic inflammation and increased risk of cancer. The molecular mechanisms for oxidative damage of DNA during inflammation remain poorly understood, however. While addressing this issue, we identified three phagocyte-dependent pathways that oxidatively damage DNA in vitro: i) the myeloperoxidase pathway begins with activated neutrophils and monocytes, the cellular hallmarks of inflammation, ii) The reactive nitrogen pathway involves macrophages and/or endothelial cells, iii) The eosinophil peroxidase pathway operates in eosinophils, which are of central importance in host responses to parasitic infection. The overall goal of this proposal is to test the hypothesis that oxidants are generated by one or more of the above pathways during inflammation nitrate and halogenate nucleobases, promoting mutagenesis and damaging cells. We will seek evidence for the operation of the pathways through complementary studies of human and mouse tissue. Our specific aims are: First, to determine whether tissue isolated from the lungs of smokers contains nucleobase oxidation products specific for the myeloperoxidase pathway, eosinophil peroxidase pathway, or reactive nitrogen pathway. Second, to use mouse models of chronic inflammation to investigate the roles of the myeloperoxidase pathway, reactive nitrogen pathway, and eosinophil peroxidase pathway in nucleobase oxidation in vivo. Third, to identify additional oxidized nucleobases generated by myeloperoxidase, reactive nitrogen species, or eosinophil peroxidase in vitro. These studies should provide insights into the molecular mechanisms of oxidative damage to DNA during inflammation.

描述（申请人提供）：活性白产生的氧化剂 血细胞对于宿主防御微生物至关重要。然而， 反应性物质会损害蛋白质和脂质，因此也可能会损害 宿主组织。此外，它们还氧化核酸，因此可以 损害基因组的完整性。这种损害可能是由于 慢性炎症与癌症风险增加之间的关联。这 炎症过程中 DNA 氧化损伤的分子机制仍然存在 然而，人们对此知之甚少。在解决这个问题时，我们确定了三个 体外氧化损伤 DNA 的吞噬细胞依赖性途径：i) 髓过氧化物酶途径始于活化的中性粒细胞和单核细胞， 炎症的细胞特征，ii) 活性氮途径涉及 巨噬细胞和/或内皮细胞，iii) 嗜酸性粒细胞过氧化物酶途径 在嗜酸性粒细胞中起作用，嗜酸性粒细胞在宿主对病毒的反应中至关重要 寄生虫感染。 该提案的总体目标是检验氧化剂是氧化剂的假设 炎症过程中由上述一种或多种途径产生的硝酸盐和 卤化核碱基，促进诱变并损伤细胞。我们将寻求 通过补充研究提供途径运作的证据 人类和小鼠组织。我们的具体目标是：首先，确定是否 从吸烟者肺部分离的组织含有核碱基氧化 髓过氧化物酶途径、嗜酸性粒细胞过氧化物酶特异性产品 途径，或活性氮途径。二、使用慢性小鼠模型 炎症以研究髓过氧化物酶途径的作用，反应性 核碱基氧化中的氮途径和嗜酸性粒细胞过氧化物酶途径 体内。第三，鉴定产生的额外氧化核碱基 体外髓过氧化物酶、活性氮或嗜酸性粒细胞过氧化物酶。 这些研究应该提供对分子机制的见解 炎症过程中 DNA 发生氧化损伤。