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.
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.
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|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|
|Chang, Shiou-Chi; Seneviratne, Uthpala I; Wu, Jie et al. (2017) 1,3-Butadiene-Induced Adenine DNA Adducts Are Genotoxic but Only Weakly Mutagenic When Replicated in Escherichia coli of Various Repair and Replication Backgrounds. Chem Res Toxicol 30:1230-1239|
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|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|
|Peng, Chunte Sam; Fedeles, Bogdan I; Singh, Vipender et al. (2015) Two-dimensional IR spectroscopy of the anti-HIV agent KP1212 reveals protonated and neutral tautomers that influence pH-dependent mutagenicity. Proc Natl Acad Sci U S A 112:3229-34|
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