GENETIC PROPERTIES OF DNA DAMAGE INDUCED BY PEROXYNITRITE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 作为用于对抗入侵病原体的化学武器的一部分，某些类型的白血球会产生反应性自由基。例如，巨噬细胞分泌超氧化物和一氧化氮，它们结合在一起产生过氧亚硝酸盐，过氧亚硝酸盐是一种能够分解成能够破坏蛋白质、脂质和DNA的物质。关于DNA，鸟嘌呤对过氧亚硝酸根特别敏感，已经确定了许多氧化和硝化的衍生物。此外，在慢性炎症部位，过氧亚硝酸盐会在较长时间内过度产生。事实上，炎症性肠综合征、结肠癌、胃癌和幽门螺杆菌感染与慢性炎症和癌症之间的联系已经确定。体外和在细菌中的研究表明，许多过氧亚硝酸盐诱导的DNA损伤具有很强的致突变性，并有不同程度的毒性。然而，为了充分了解过氧亚硝酸盐过度生产的遗传后果，并揭示其对癌症的贡献，我们将研究这些DNA损伤在哺乳动物系统中的生物处理。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. As part of the chemical armamentarium used to combat invading pathogens, certain types of white blood cells produce reactive radicals. For instance, macrophages secrete superoxide and nitric oxide which combine to generate peroxynitrite, an agent that decomposes into species capable of damaging proteins, lipids, and DNA. With regard to DNA, guanine is particularly sensitive to peroxynitrite and numerous oxidized and nitrated derivatives have been identified. Furthermore, at sites of chronic inflammation, peroxynitrite is overproduced for prolonged periods of time. Indeed, a link between chronic inflammation and cancer has been established for inflammatory bowel syndrome ,colon cancer, gastric cancer, and Helicobacter pylori infection. Work both in vitro and in bacteria has shown that many of the peroxynitrite-induced DNA lesions are potently mutagenic and have varying degrees of toxicity. However, in order to understand fully the genetic consequences of peroxynitrite overproduction, and to unravel its contributions to cancer, we will examine the biological processing of these DNA lesions within a mammalian system.