Pathways for oxidative damage of DNA by phagocytes

描述（由申请人提供）：活化白色产生的氧化剂 血细胞对于宿主抵抗微生物至关重要。然而，在这方面， 活性物质破坏蛋白质和脂质，因此也可能破坏 宿主组织此外，它们还氧化核酸，因此可以 危及基因组的完整性。这种损害可以解释 慢性炎症与癌症风险增加之间的关联。的 炎症期间DNA氧化损伤的分子机制仍然存在 然而，人们对此却知之甚少。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： 髓过氧化物酶途径始于活化的中性粒细胞和单核细胞， 炎症的细胞标志，ii）活性氮途径涉及 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 寄生虫感染 这项提案的总体目标是检验氧化剂是 在炎症过程中由一种或多种上述途径产生硝酸盐， 卤化核碱基，促进诱变和损伤细胞。我们将寻求 通过对以下方面的补充研究， 人类和小鼠组织。我们的具体目标是：第一，确定是否 从吸烟者的肺中分离的组织含有核碱基氧化 髓过氧化物酶途径特异性产物，嗜酸性粒细胞过氧化物酶 反应性氮途径（reactive nitrogen pathway）二、采用小鼠慢性 炎症研究髓过氧化物酶途径的作用，反应性 氮途径和嗜酸性粒细胞过氧化物酶途径在核碱基氧化中的作用。 vivo.第三，为了鉴定由以下物质产生的另外的氧化核碱基： 髓过氧化物酶、活性氮物质或嗜酸性粒细胞过氧化物酶。 这些研究应该提供深入了解的分子机制， 炎症过程中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.