Leukocyte-Generated Oxidants and DNA Mutagenesis

Cleveland Clinic Lerner Col/Med-Cwru, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): A clinical link between inflammation, and the development of certain cancers is well known. For example, persons with ulcerative colitis, a form of inflammatory bowel disease have a 14-25% increased risk of developing colon cancer. While numerous in vitro studies suggest leukocyte-generated oxidants exert genotoxic effects that could promote cancer development, direct demonstration of this in vivo is lacking. This proposal will test the hypothesis that phagocyte generated oxidants, specifically those produced by the NADPH oxidase complex and myeloperoxidase, contribute to DNA mutagenesis and cancer development, thus linking inflammation and cancer. This proposal will examine the contribution of oxidative stress to DNA mutagenesis in animal models. It will address our understanding of the pathways involved in oxidative damage in vivo using a combination of molecular biology and biochemical approaches. Collectively, these studies will elucidate the chemical pathways involved in DNA damage and their biological outcomes.