The influence of DNA repair on inflammation associated carcinogenesis

DNA修复对炎症相关癌发生的影响

• 批准号: 8225283
• 负责人: LEONA D. SAMSON
• 金额: $ 33.81万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225283
• 关键词: Alkylation; Animals; Base Excision Repairs; Cancer Burden; Chronic; Colon Carcinoma; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA glycosylase; DNA repair protein; Deamination; Deletion Mutation; Etiology; Genetic; Head; Human; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Knockout Mice; Lesion; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Molecular; Monitor; Mus; Nitrogen; Oxygen; Pathway interactions; Phagocytes; Play; Research; Role; Skin Cancer; Tissues; Transgenic Mice; antimicrobial drug; base; cancer risk; cancer type; carcinogenesis; falls; in vivo; insight; macrophage; mouse model; mutant; neutrophil; oxidation; public health relevance; repaired; response; tumor; tumorigenesis

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.

描述（由申请人提供）：据估计，大约20％的全球癌症负担来自患有慢性炎症反应的人。这种慢性炎症已被接受为许多不同类型癌症的病因的重要原因。在慢性炎症期间，巨噬细胞，中性粒细胞和其他吞噬细胞会产生活性氧和氮种（RONS）作为正常的抗菌剂，以帮助消除感染，而我们拟议的研究的主要部分将集中在Rons在肿瘤中起作用的作用。已知RON可以直接通过氧化，脱氨基和间接地通过烷基化损伤诱导受损的DNA碱基。我们将探讨这种受损的DNA碱基的修复如何通过检查众多（或更多）众多DNA修复蛋白（AAG，ABH2，ABH3，MYH，MYH，OGG1和MBD4）中缺乏的小鼠来影响致癌反应。我们将在慢性炎症介导的癌变的已建立小鼠模型下检查这些突变动物：AOM+DSS治疗，IL10无效小鼠，MDR2 NULL小鼠或I：B-1-SR转基因小鼠。选择了这些炎症模型，以检查DNA修复在炎症介导的癌变中的作用的普遍性，通过检查DNA修复对通过不同机制和不同组织中产生的肿瘤的贡献。拟议研究的具体目的属于以下三个标题：（i）探索AAG在抑制与慢性炎症相关的致癌作用中的作用； （ii）探讨其他DNA修复分子/途径在防御慢性炎症引起的致癌作用中的作用； （iii）检查DNA修复缺乏动物的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基本贡献。此外，它将为我们的自然防御能力提供更多的见解，以防止环境和内源性DNA损害剂的有毒和致癌作用。 公共卫生相关性：慢性炎症对人类（和小鼠）的致癌作用的贡献已得到充分确立。然而，对于DNA修复在炎症诱导的致癌作用中的推定作用知之甚少，我们建议研究DNA修复对癌变的贡献。了解DNA修复如何有助于致癌，将为慢性炎症增加癌症的机会以及确定降低癌症风险的可能方法提供洞察力。