MUTAGENESIS AND TOXICITY OF PEROXYNITRITE-INDUCED DNA LESIONS IN HUMAN CELLS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 某些类型的白色血细胞产生活性自由基，作为对抗入侵病原体的化学武器的一部分。 例如，巨噬细胞分泌超氧化物和一氧化氮，它们联合收割机产生过氧亚硝酸盐，一种分解成能够破坏蛋白质、脂质和DNA的物质的试剂。 对于DNA，鸟嘌呤对过氧亚硝酸盐特别敏感，并且已经鉴定了许多氧化和硝化衍生物。 此外，在慢性炎症部位，过氧亚硝酸盐长时间过量产生。 事实上，慢性炎症和癌症之间的联系已经被确定为炎症性肠综合征和结肠癌，以及幽门螺杆菌感染和胃癌。 在体外和细菌中的工作表明，许多过氧亚硝酸盐诱导的DNA损伤是潜在的致突变性，并具有不同程度的毒性。 然而，为了充分了解过氧亚硝酸盐过量产生的遗传后果，并揭示其对癌症的贡献，我们将研究哺乳动物系统内这些DNA损伤的生物学处理。

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 and colon cancer and also for Helicobacter pylori infection and gastric cancer. 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.