The broad scientific goal of this interactive research program is to evolve a systematic biochemical understanding of how the consumption of fibers, fats, and proteins results in colonic epithelial cells that are more or less susceptible to chemical carcinogens. The focus of this proposal is on short chain fatty acids (SCFA) which are the products of fiber fermentation. Using cells from both carcinogen-treated and saline control animals, we propose to characterize how uptake of SCFA into colonocytes changes the biochemistry of these cells in such a way that their proliferative status is altered. The three important changes in biological/biochemical states that will be investigated are: (1) changes in intracellular pH; (2) changes in colonocyte metabolism (including energy status); and (3) changes in membrane lipids that result in changes in signal transduction pathways (specifically Protein Kinase C, isoforms and subcellular localization). Since there is good evidence that the effect of SCFA on colonocytes is different in normal cells vs transformed cells, experiments will be conducted in both cell types. Further, since the proximal and distal colon have different cell kinetics and SCFA absorption patterns, they will be treated as separate tissues. The data generated will elucidate how intracellular pH, colonocyte metabolism, and intracellular signaling mechanisms, which regulate epithelial cytokinetics, are influenced by different types and amounts of SCFA characterization of each part of this complex process should provide important information on the basic biology of colonocytes. Elucidation of the fundamental mechanisms regulating colonic epithelial cytokinetics is essential if diet is to be established as a legitimate colon cancer prevention strategy.
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