Our working hypothesis in this Program is that chemical species generated by phagocytes at sites of inflammation represent a causative link to human disease. Project 1 focuses on reactions of the chemical mediators of inflammation with DNA, lipids, and proteins in epithelial cells, which lead to altered physiology, cell death and mutations associated with cancer. The objectives are to explore the mechanisms of this damage, to develop surrogate markers of the labile inflammatory mediators, and to develop candidate biomarkers of inflammation. The methods and results from Project 1 will be translated to Projects 2, 3, and 4 to test hypotheses about the link between chemical changes and biological effects in cell and animal models. In the last funding period, we developed methods to quantify DNA, RNA and protein damage products that represent key markers of inflammation chemistry resulting from neutrophil and macrophage activity, including the protein lesions 3-chloro- and 3-nitro-tyrosine, and DNA and RNA damage caused by oxidation (8-oxo-guanine, spiroiminodihydantoin, guanidinohydantoin, oxazolone), deamination (xanthine, hypoxanthine), halogenation (5-chlorocytidine) and electrophile reactions (etheno adducts of A, G and C). These analytical methods are now mature enough to be moved into Core A as routine assays. We now propose to expand the development and application of biomarker candidates to test a variety of hypotheses that have arisen from results obtained in the last funding period.

Public Health Relevance

Inflammation is now recognized as a major factor in the etiology of many types of cancer. The proposed research will open new understanding of the role of the chemical changes to proteins and DNA brought about by the immune cells attracted to the site of inflammation. The overall chemical damage contributes strongly to the process leading to cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA026731-35A1
Application #
8666940
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (J1))
Project Start
1997-01-15
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
35
Fiscal Year
2014
Total Cost
$247,576
Indirect Cost
$88,874
Name
Massachusetts Institute of Technology
Department
Type
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Gu, Chen; Ramos, Jillian; Begley, Ulrike et al. (2018) Phosphorylation of human TRM9L integrates multiple stress-signaling pathways for tumor growth suppression. Sci Adv 4:eaas9184
Wadduwage, Dushan N; Kay, Jennifer; Singh, Vijay Raj et al. (2018) Automated fluorescence intensity and gradient analysis enables detection of rare fluorescent mutant cells deep within the tissue of RaDR mice. Sci Rep 8:12108
Tajai, Preechaya; Fedeles, Bogdan I; Suriyo, Tawit et al. (2018) An engineered cell line lacking OGG1 and MUTYH glycosylases implicates the accumulation of genomic 8-oxoguanine as the basis for paraquat mutagenicity. Free Radic Biol Med 116:64-72
Rothenberg, Daniel A; Taliaferro, J Matthew; Huber, Sabrina M et al. (2018) A Proteomics Approach to Profiling the Temporal Translational Response to Stress and Growth. iScience 9:367-381
Wang, Xin; Garcia, Carlos T; Gong, Guanyu et al. (2018) Automated Online Solid-Phase Derivatization for Sensitive Quantification of Endogenous S-Nitrosoglutathione and Rapid Capture of Other Low-Molecular-Mass S-Nitrosothiols. Anal Chem 90:1967-1975
Chan, Cheryl; Pham, Phuong; Dedon, Peter C et al. (2018) Lifestyle modifications: coordinating the tRNA epitranscriptome with codon bias to adapt translation during stress responses. Genome Biol 19:228
Fedeles, Bogdan I (2017) G-quadruplex-forming promoter sequences enable transcriptional activation in response to oxidative stress. Proc Natl Acad Sci U S A 114:2788-2790
Townsend, Todd A; Parrish, Marcus C; Engelward, Bevin P et al. (2017) The development and validation of EpiComet-Chip, a modified high-throughput comet assay for the assessment of DNA methylation status. Environ Mol Mutagen 58:508-521
Kimoto, Takafumi; Kay, Jennifer E; Li, Na et al. (2017) Recombinant cells in the lung increase with age via de novo recombination events and clonal expansion. Environ Mol Mutagen 58:135-145
Edrissi, Bahar; Taghizadeh, Koli; Moeller, Benjamin C et al. (2017) N6-Formyllysine as a Biomarker of Formaldehyde Exposure: Formation and Loss of N6-Formyllysine in Nasal Epithelium in Long-Term, Low-Dose Inhalation Studies in Rats. Chem Res Toxicol 30:1572-1576

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