We have generated a Gpx1/2-KO mouse line, with combined disruption of both Gpx1 and Gpx2 genes, which encode two intracellular Se-dependent glutathipne peroxidases. These mice have ileocolitis and cancer, resembling increased cancer risks of human patients having either Crohn's disease (CD) or ulcerative colitis (UC). Based on our mouse model, we have proposed that oxidative stress makes them susceptible to inflammation, which in turn generates more damaging reactive oxygen species (ROS), and leads to gene mutations and cancer. To provide evidence to support our hypotheses, we plan to do the following: 1) To determine whether mutations of two major tumor suppressor genes, Ape and Tp53, in intestinal mucosa of Gpx1/2-KO mice are correlated with microflora, inflammation, and mouse genetic background, and whether the mutation spectra reflect oxidative stress as an initiating factor. 2) To determine whether oxidative stress, inflammation, microflora, and mouse genetic background also affects global gene mutations determined with two silent reporter genes, ell and lad, in Gpx1/2-KO mice. 3) To determine whether pro-oxidant bacteria, Enterococcus faecalis and pro-inflammatory dextran sulfate sodium can increase oxidative stress, gene mutations, and cancer in germ free and conventionally housed Gpx1/2-KO mice. 4) To determine whether anti-oxidant or anti-inflammatory agents, such as diphenylene iodonium (DPI), and probiotic bacteria can decrease gene mutations and cancer incidence in Gpx1/2-KO mice. Upon completion of this study, we will have clarified the role of oxidative stress as a causative factor for inflammatory bowel disease (IBD), which includes both CD and UC. Studies on the timing, sequence and spectrum of gene mutations in this mouse model would have provided a new insight into the etiology of human IBD. Our work should help to devise more effective strategies to prevent and treat IBD as well as intestinal and colonic cancer. About a million Americans suffer IBD, and have higher risks for cancer. Study of this novel mouse IBD model may provide new information on the etiology and treatment of IBD and IBD-related cancer. ? ?
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