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体。这种慢性炎症被认为是许多不同类型癌症病因的重要因素。在慢性炎症中，巨噬细胞、中性粒细胞和其他吞噬细胞产生活性氧和活性氮（RONS）作为正常的抗菌剂来协助消除感染，我们拟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、脱氨或间接通过烷基化损伤诱导DNA碱基受损。我们将通过检测多种DNA修复蛋白（Aag、Abh2、Abh3、Myh、Ogg1和Mbd4）缺乏的小鼠，探讨这些受损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癌变小鼠模型下检测这些突变动物：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，通过检查DNA修复对通过不同机制和不同组织产生的肿瘤的贡献，来检查DNA修复在炎症介导的致癌作用中的普遍性。本研究的具体目的有以下三个方面：(1)探索Aag在抑制慢性炎症相关癌变中的作用；（II）探索其他DNA修复分子/途径在预防慢性炎症诱导癌变中的作用；（III）研究DNA修复缺陷动物中致癌增加的分子后果。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的贡献。此外，它将为我们对环境和内源性DNA损伤剂的有毒和致癌作用的天然防御提供额外的见解。

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. PUBLIC HEALTH RELEVANCE: The contribution of chronic inflammation to carcinogenesis in humans (and mice) has been well- established. However, less is known about the putative role of DNA repair in inflammation-induced carcinogenesis, and we propose to investigate the contribution of DNA repair to carcinogenesis. Understanding how DNA repair contributes to carcinogenesis will provide insights into the mechanism by which chronic inflammation increases the chance of cancer as well as identify possible approaches to decrease cancer risk.