The long-term objective of this Program is to develop an understanding of the chemical mechanisms in the causal relationship of inflammation to cancer. Within the broad theme of defining the quantitative interplay between the chemistry and biology of inflammation, four integrated projects translate the research from a fundamental understanding of nitric oxide (NO) and myeloperoxidase-derived chemistry in vitro, to cell and animal models of inflammation-induced cell dysfunction, mutagenesis and cancer, and then to mechanisms of inflammatory bowel disease, and colon cancer in humans. The proposed Program builds on our recent discoveries of critical roles for phagocyte-mediated NO and chlorination chemistry, the complex interplay between DNA repair and cell response pathways, and a critical role for mechanisms of microbial pathogenesis in infection-mediated inflammation and cancer. Our central hypothesis is that specific subsets of inflammatory cells generate chemicals that cause mutations, other forms of cellular damage, and alteration of key pathways for growth and survival that collectively, and augmented by bacterial genotoxins, lead to cancer. There are 4 Projects and 3 Cores.
The Specific Aims of project 1 are to develop, validate and apply analytical and 'omic methods to identify and measure molecular changes reflecting the full range of inflammation chemistry. Molecular changes identified in this manner will be applied to cell models, mouse models and human tissues. Project 2 is designed to define the mutagenic and lethal properties of specific DNA lesions identified in project 1, whether inflammation also causes damage to nucleotide pools, and whether it reprograms epigenetic patterns in the genomes of cells.
The Specific Aims of project 3 are to characterize the role of S-nitrosation in the regulation of DNA repair and growth and survival pathways, and to investigate the role of neutrophil chlorination in mutagenesis.
The Specific Aims of project 4 are to define the impact of microbial pathogens and their genotoxic products on DNA damage and repair, as well as the impact of the CDT gene of Helicobacter species on inflammation, mutagenesis and cancer in vivo through studies in mouse models. These four major projects are entirely dependent on support by three Cores. Core A provides both the analytical chemical and cell culture support required across the Projects. Core B is the focus of the animal studies, pathology, immunohistochemistry, etc. Core C provides administrative and statistical support and direction for the overall Program, contact with collaborators, and interaction with the External Advisory Committee.
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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