Chronic inflammation of the gastrointestinal (GI) tract is associated with increased incidence of colon cancer. Reactive oxygen and nitrogen species, generated in response to inflammation, are known to contribute to mutagenesis. Selenium-dependent glutathione peroxidase (GPx) is one of the enzymes involved in reducing hydrogen peroxide. GPx is a fundamental enzyme for protection of polyunsaturated lipids in biological membranes. In addition to its essential role in GPx activity, selenium may have separate anti-oxidant and anti-cancer properties and may act as an anti-inflammatory agent through effects on p38 MAPK and NF-?B. A number of studies have demonstrated cancer chemopreventive effects of selenium supplementation; however, the mechanisms by which selenium suppresses tumorigenesis are still unknown. Low selenium levels are also associated with the digestive form of Chagas' disease in humans suggesting a role for selenium in inflammation of the GI tract. The goals of this exploratory/developmental research project are to use noninvasive magnetic resonance imaging (MRI) methods in combination with micro-PET and biological assays to evaluate the role of selenium supplementation in mouse models of inflammation and cancer. Two types of mouse models will be used. The first is the Trypanosoma cruzi infected mouse model of Chagas' disease. We have performed extensive cardiac imaging studies on these mice which develop cardiomegaly in addition to megacolon and megaesophagus. This disease involves inflammation of the GI tract without the development of tumors. The second type of mouse model is GI tract cancer. The Apc heterozygote and Muc2/p21 double mutation mice are excellent models available for the study of tumors in the GI tract.
Two specific aims will be addressed in this project.
Aim 1 will evaluate the role of selenium in GI Tract inflammation in mice infected with T. cruzi.
Aim 2 will evaluate the role of selenium in development of tumors in mouse models of intestinal cancer. The methodology developments and results acquired in this project will be used to guide future studies aimed at evaluating the role of therapeutic agents and anti-oxidants in other inflammatory diseases and cancer of the GI tract. KEY ? ? ?
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