MECHANISM OF CARCINOGENESIS BY PEROXISOME PROLIFERATORS

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My immediate and long-term career objectives are to actively engage in research in the area of carcinogenesis. I plan to study the mechanisms by which peroxisome proliferators induce hepatocellular carcinomas. I am testing the hypotheses that peroxisome proliferators induce hepatocellular carcinomas by 1) inducing oxidative DNA damage, 2) increasing long-term cell proliferation, or 3) altering eicosanoid metabolism. We will compare ciprofibrate with the unusual peroxisome proliferator perfluorodecanoic acid, which, unlike most other peroxisome proliferators, inhibits peroxisomal beta-oxidation, increases glutathione concentrations, and does not have promoting activity, for their abilities to produce the above changes. Transgenic mice will be produced with liver specific expression of peroxisome proliferator-induced genes so that the genetic change that produces biochemical changes induced by peroxisome proliferators can be identified.