Pathways for oxidative damage of DNA by phagocytes

描述(申请人提供)：由活性白色生成的氧化剂 血细胞是抵御微生物的关键。然而， 活性物种损害蛋白质和脂质，因此也可能损害 宿主组织。此外，它们还可以氧化核酸，因此可以 损害了基因组的完整性。这种损害可能解释了 慢性炎症与癌症风险增加之间的关系。这个 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的吞噬细胞依赖途径：i) 髓过氧化物酶途径始于激活的中性粒细胞和单核细胞， 炎症的细胞特征，II)反应氮途径包括 巨噬细胞和/或内皮细胞，III)嗜酸性粒细胞过氧化物酶途径 在嗜酸性粒细胞中工作，嗜酸性粒细胞在宿主对 寄生虫感染。 这项提议的总体目标是检验氧化剂是 在炎症过程中由上述一个或多个途径产生的硝酸盐和 卤化碱基，促进突变和破坏细胞。我们将寻求 通过补充性研究证明通路的运行 人和老鼠的组织。我们的具体目标是：第一，确定是否 从吸烟者的肺中分离出的组织含有核苷酸碱基氧化 髓过氧化物酶途径的特异性产物，嗜酸性粒细胞过氧化物酶 途径，或活性氮途径。第二，采用慢性阻塞性肺疾病小鼠模型 炎症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 活着。第三，鉴定额外的氧化碱基 髓过氧化物酶，活性氮物种，或体外嗜酸性粒细胞过氧化物酶。 这些研究应该能为深入了解其分子机制提供帮助。 炎症过程中对DNA的氧化损伤。

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.