The influence of DNA repair on inflammation associated carcinogenesis

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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.