The influence of DNA repair on inflammation associated carcinogenesis

描述(由申请人提供)：据估计，全球约20%的癌症负担来自患有慢性炎症反应的个人。这种慢性炎症被认为是许多不同类型癌症的重要致病因素。在慢性炎症期间，巨噬细胞、中性粒细胞和其他吞噬细胞产生活性氧和氮物种(RONS)作为正常的抗菌剂，以帮助消除感染，我们拟议的研究的主要部分将集中在RONS在肿瘤发生中的作用。已知RON可直接通过氧化、脱胺和间接通过烷基化损伤来诱导DNA碱基损伤。我们将通过检测许多DNA修复蛋白(AAG、Abh2、Abh3、Myh、Ogg1和Mbd4)中的一种(或多种)缺陷的小鼠，来探索这种受损DNA碱基的修复如何影响致癌反应。我们将在已建立的慢性炎症介导的致癌小鼠模型下研究这些突变动物：AOM+DSS治疗、IL10缺失小鼠、mdr2缺失小鼠或I：B-1-SR转基因小鼠。选择这些炎症模型，通过检测DNA修复对不同机制和不同组织中发生的肿瘤的贡献，来检查DNA修复在炎症介导的癌症发生中所起作用的普遍性。拟议研究的具体目标如下：(I)探索AAG在抑制与慢性炎症相关的癌变中的作用；(Ii)探索其他DNA修复分子/途径在预防慢性炎症诱导的癌变中的作用；以及(Iii)研究DNA修复缺陷动物癌变增加背后的分子后果。这些研究将为我们理解DNA修复在慢性炎症介导的癌变中的作用提供重要贡献。此外，它将为我们对环境和内源性DNA损伤剂的毒性和致癌影响的自然防御提供更多的洞察力。

DESCRIPTION (provided by applicant): It has been estimated that approximately 20% of the global cancer burden arises from individuals suffering chronic inflammatory responses. Such chronic inflammation is becoming accepted as an important contributor to the etiology of many different types of cancer. During chronic inflammation, macrophages, neutrophils, and other phagocytic cells generate reactive oxygen and nitrogen species (RONS) as normal antimicrobial agents to assist in eliminating infection and a major part of our proposed research will focus on the role that RONS play in tumorigenesis. RONS are known to induce damaged DNA bases, either directly via oxidation, deamination and indirectly via alkylation damage. We will explore how the repair of such damaged DNA bases influences the carcinogenic response by examining mice deficient in one (or more) of numerous DNA repair proteins (Aag, Abh2, Abh3, Myh, Ogg1, and Mbd4). We will examine these mutant animals under established mouse models of chronic inflammation-mediated carcinogenesis: AOM+DSS treatment, IL10 null mice, Mdr2 null mice, or the I:B-1-SR transgenic mice. These models of inflammation were chosen to examine the generality of the role of DNA repair in inflammation-mediated carcinogenesis by examining the contribution of DNA repair to tumors that arise via different mechanisms and in different tissues. The Specific Aims of the proposed research fall under the following three headings: (I) explore the role of Aag in suppressing carcinogenesis associated with chronic inflammation; (II) explore the role of other DNA repair molecules/pathways in the protection against chronic inflammation-induced carcinogenesis; and (III) examine the molecular consequences behind increased carcinogenesis in DNA repair deficient animals. These studies will provide essential contributions to our understanding of the role of DNA repair in chronic inflammation- mediated carcinogenesis. Further, it will provide additional insight into our natural defenses against the toxic and carcinogenic effects of both environmental and endogenous DNA damaging agents.