Project 4 In order to investigate the mechanisms by which inflammation, oxidative stress, and nitric oxide in particular contribute to cancer risk, we have developed a series of mouse models of colitis and colitis-associated cancer. We will use highly susceptible compound mutant mice deficient for interleukin 10 (IL10) and recombination activating gene 2 (Rag2) on a 129/SvEv background. These 129/SvEv IL10[-/-]Rag[-/-] mice develop lesions that resemble inflammatory bowel disease (IBD) and cancer when infected with Helicobacter hepaticus or after adoptive transfer with CD4*CD45RB[high] effector T cells (Teff). We will also use IL10[-/-] mice on a C57BL/6 background infected with Helicobacter trogontum and wild type C57BL/6 mice infected with Citrobacter rodentium. For all three mouse models, the gpt delta reporter transgene will be used to quantify and characterize somatic mutations that arise in vivo. A novel Fluorescent Yellow Direct Repeat (FYDR) transgene will also be generated in order to quantify recombination events in vivo. We will characterize the role of inducible nitric oxide synthase (iNOS) in 129/SvEv IL10[-/-]Rag[-/-] mice infected with H. hepaticus that develops a rapid onset of colitis-associated cancer, C57BL/6 IL10[-/-] mice infected with H. trogontum that develops IBD, and C57BL/6 mice infected with C. rodentium that develops a self-limiting colitis. This will be accomplished by pharmacologic inhibition of NOS enzymes as well as by crossing our C57BL/6 models with iNOS[-/-] mice. Depletion experiments will also be carried out to ascertain the role of neutrophils and macrophages in colitis and cancer in these model systems. These experiments will provide specimens for the other Projects in this Program in order to validate computational models, characterize chemical biomarkers, and establish the role of DNA damage and repair in mutagenesis. By establishing the role of nitric oxide produced by inflammatory cells and by epithelial cells in the large intestine, we will gain a better understanding of the mechanistic basis of cancer risk in IBD, and in mucosal inflammation in general. These studies and the interactions with the other Projects in the Program should translate into new strategies to prevent the initiation or delay the progression of inflammation-associated cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Massachusetts Institute of Technology
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Whary, Mark T; Muthupalani, Sureshkumar; Ge, Zhongming et al. (2014) Helminth co-infection in Helicobacter pylori infected INS-GAS mice attenuates gastric premalignant lesions of epithelial dysplasia and glandular atrophy and preserves colonization resistance of the stomach to lower bowel microbiota. Microbes Infect 16:345-55
Kiraly, Orsolya; Gong, Guanyu; Roytman, Megan D et al. (2014) DNA glycosylase activity and cell proliferation are key factors in modulating homologous recombination in vivo. Carcinogenesis 35:2495-502
Lertpiriyapong, Kvin; Handt, Laurence; Feng, Yan et al. (2014) Pathogenic properties of enterohepatic Helicobacter spp. isolated from rhesus macaques with intestinal adenocarcinoma. J Med Microbiol 63:1004-16
Ge, Zhongming; Feng, Yan; Muthupalani, Sureshkumar et al. (2014) Helicobacter hepaticus cholesterol-?-glucosyltransferase is essential for establishing colonization in male A/JCr mice. Helicobacter 19:280-8
Shrivastav, Nidhi; Fedeles, Bogdan I; Li, Deyu et al. (2014) A chemical genetics analysis of the roles of bypass polymerase DinB and DNA repair protein AlkB in processing N2-alkylguanine lesions in vivo. PLoS One 9:e94716
Fox, James G; Wang, Timothy C (2014) Dietary factors modulate Helicobacter-associated gastric cancer in rodent models. Toxicol Pathol 42:162-81
Kumar, Yadunanda; Liang, Cui; Limmon, Gino V et al. (2014) Molecular analysis of serum and bronchoalveolar lavage in a mouse model of influenza reveals markers of disease severity that can be clinically useful in humans. PLoS One 9:e86912
Singh, Vipender; Peng, Chunte Sam; Li, Deyu et al. (2014) Direct observation of multiple tautomers of oxythiamine and their recognition by the thiamine pyrophosphate riboswitch. ACS Chem Biol 9:227-36
Li, Deyu; Fedeles, Bogdan I; Singh, Vipender et al. (2014) Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2'-deoxycytidine. Proc Natl Acad Sci U S A 111:E3252-9
Swennes, Alton G; Sheh, Alexander; Parry, Nicola M A et al. (2014) Helicobacter hepaticus infection promotes hepatitis and preneoplastic foci in farnesoid X receptor (FXR) deficient mice. PLoS One 9:e106764

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