It has been estimated that about 20% of the global cancer occurs in individuals suffering chronic inflammatory responses. Such chronic inflammation is becoming accepted as an important contributor to the etiology of many different tumor types. A major part of the proposed research will focus on the role that the reactive oxygen and nitrogen species (RONS) that inevitably accompany chronic inflammation play in tumorigenesis. RONS are known to induce damaged DNA bases, and we will explore how the repair of such damaged DNA bases influences the carcinogenic response of animals under chronic inflammatory conditions. A number of mouse models for DNA repair deficiencies (Aag, Abh2, Myh, Ogg1 and Mbd4 null mice) will be combined with one of the following mouse models for chronic inflammation-associated carcinogenesis: IL10 and Mdr2 null mice, and the I:B-1-super-repressor transgenic mice. In addition, using newly derived transgenic mice, we will explore the consequences of expressing the Aag DNA glycosylase at different levels in various tissues following up on studies that indicate increased expression of the DNA repair enzyme predisposes animals to tumorigenesis.
The Specific Aims of the proposed research fall under the following two headings: (I) Explore the role of DNA repair in suppressing carcinogenesis associated with chronic inflammation;and (II) Explore the phenotypic consequences of expressing the Aag transgene in different mouse tissues. These studies will contribute to our understanding of our natural defenses against the toxic and carcinogenic effects of both environmental and endogenous DNA damaging agents.
Chronic inflammation contributes to carcinogenesis in humans (and mice) and we propose to dissect the underlying mechanisms of how this happens. In addition, increased spontaneous mutation rates render humans (and mice) cancer prone and we propose to investigate novel mechanisms that influence spontaneous mutation rates. Understanding how these mechanisms increase cancer risk should lead to the development of ways to decrease cancer risk.
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