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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA026731-34
Application #
8567216
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
34
Fiscal Year
2013
Total Cost
$289,228
Indirect Cost
$116,424
Name
Massachusetts Institute of Technology
Department
Type
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Chen, Fangyi; Tang, Qi; Bian, Ke et al. (2016) Adaptive Response Enzyme AlkB Preferentially Repairs 1-Methylguanine and 3-Methylthymine Adducts in Double-Stranded DNA. Chem Res Toxicol 29:687-93
Seneviratne, Uthpala; Nott, Alexi; Bhat, Vadiraja B et al. (2016) S-nitrosation of proteins relevant to Alzheimer's disease during early stages of neurodegeneration. Proc Natl Acad Sci U S A 113:4152-7
Chang, Shiou-chi; Fedeles, Bogdan I; Wu, Jie et al. (2015) Next-generation sequencing reveals the biological significance of the N(2),3-ethenoguanine lesion in vivo. Nucleic Acids Res 43:5489-500
Shen, Zeli; Feng, Yan; Rickman, Barry et al. (2015) Helicobacter cinaedi induced typhlocolitis in Rag-2-deficient mice. Helicobacter 20:146-55
Fedeles, Bogdan I; Freudenthal, Bret D; Yau, Emily et al. (2015) Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer. Proc Natl Acad Sci U S A 112:E4571-80
Singh, Vipender; Fedeles, Bogdan I; Essigmann, John M (2015) Role of tautomerism in RNA biochemistry. RNA 21:1-13
Chan, Clement T Y; Deng, Wenjun; Li, Fugen et al. (2015) Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes. Chem Res Toxicol 28:978-88
Iverson, Nicole M; Strano, Michael S; Wogan, Gerald N (2015) In Vivo Delivery of Nitric Oxide-Sensing, Single-Walled Carbon Nanotubes. Curr Protoc Chem Biol 7:93-102
Zeiger, Errol; Gollapudi, Bhaskar; Aardema, Marilyn J et al. (2015) Opportunities to integrate new approaches in genetic toxicology: an ILSI-HESI workshop report. Environ Mol Mutagen 56:277-85
Kiraly, Orsolya; Gong, Guanyu; Olipitz, Werner et al. (2015) Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo. PLoS Genet 11:e1004901

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