The overall hypotheses to be tested in this program is that DNA damage, mutation, and cytotoxicity will arise as a result of nitrosative deamination, NO radical reactions, and oxygen radical damage when target cells are exposed to generator cells that produce NO. Depending upon the dose rate, total dose, types of cells, and other circumstances, NO may drive cells into apoptosis through multiple pathways, or inhibit apoptosis, and enhance mutation through damage to bases, strand breaks, and cross-links. In the first Project we will develop mathematical models of NO, develop the link between chemical reactions of NO and mutagenesis and gene deletion, diffusion and chemistry in mono- and multicellular systems. This will help define the chemical species that attack cells and their constituents. In the next Project we will analyze the nature of chemical damage and modification of DNA and proteins that will be used to ultimately develop a set of biomarkers that will be useful in clinical or epidemiological studies. In the next Project the overall goal will be to extend out understanding of the role of NO in endogenous mutagenic processes in cells and in animals, and in multiple target genes. The goal of the last Project will be to define the role of free radical chemistry in the cytotoxic potential of NO. The specific targets are ribonucleotide reductase (a key to cytostasis), thioredoxin (a key to redox signaling and reduction of disulfide groups in critical enzymes), and thiodoxin reductase. The first Core is the center of development and application of new and existing analytical methods. The next Core is the center of development and application of new animal models. Together the individual projects and cores will create a useful paradigm for dealing with pathophysiological situations characterized by overproduction of NO. This is important for many health problems, including cancer, autoimmune and inflammatory diseases, neurological injury, and aging. Our work will lead to a better understanding of how to develop a rational approach to chemoprevention of these processes, and to provide a set of biomarkers that may be used to analyze the chemical origin of lesions in the human population.
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