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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-ONC-L (02))
Program Officer
Daschner, Phillip J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
City of Hope/Beckman Research Institute
United States
Zip Code
Chu, Fong-Fong; Esworthy, R Steven; Doroshow, James H et al. (2017) Deficiency in Duox2 activity alleviates ileitis in GPx1- and GPx2-knockout mice without affecting apoptosis incidence in the crypt epithelium. Redox Biol 11:144-156
Esworthy, Robert S; Kim, Byung-Wook; Chow, Joni et al. (2014) Nox1 causes ileocolitis in mice deficient in glutathione peroxidase-1 and -2. Free Radic Biol Med 68:315-25
Krehl, Susanne; Loewinger, Maria; Florian, Simone et al. (2012) Glutathione peroxidase-2 and selenium decreased inflammation and tumors in a mouse model of inflammation-associated carcinogenesis whereas sulforaphane effects differed with selenium supply. Carcinogenesis 33:620-8
Kim, Byung-Wook; Esworthy, R Steven; Hahn, Maria A et al. (2012) Expression of lactoperoxidase in differentiated mouse colon epithelial cells. Free Radic Biol Med 52:1569-76
Esworthy, R Steven; Kim, Byung-Wook; Rivas, Guillermo E et al. (2012) Analysis of candidate colitis genes in the Gdac1 locus of mice deficient in glutathione peroxidase-1 and -2. PLoS One 7:e44262
Esworthy, R Steven; Kim, Byung-Wook; Larson, Garrett P et al. (2011) Colitis locus on chromosome 2 impacting the severity of early-onset disease in mice deficient in GPX1 and GPX2. Inflamm Bowel Dis 17:1373-86
Dittrich, A M; Meyer, H-A; Krokowski, M et al. (2010) Glutathione peroxidase-2 protects from allergen-induced airway inflammation in mice. Eur Respir J 35:1148-54
Florian, Simone; Krehl, Susanne; Loewinger, Maria et al. (2010) Loss of GPx2 increases apoptosis, mitosis, and GPx1 expression in the intestine of mice. Free Radic Biol Med 49:1694-702
Esworthy, R Steven; Smith, David D; Chu, Fong-Fong (2010) A Strong Impact of Genetic Background on Gut Microflora in Mice. Int J Inflam 2010:986046
Gao, Qiang; Esworthy, R Steven; Kim, Byung-Wook et al. (2010) Atherogenic diets exacerbate colitis in mice deficient in glutathione peroxidase. Inflamm Bowel Dis 16:2043-54

Showing the most recent 10 out of 13 publications