Gene modulation during peroxisome proliferator-induced hepatocarcinogenesis

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dc.contributor.advisor John M. Cullen, Chair en_US
dc.contributor.advisor Russell C. Cattley, Co-Chair en_US
dc.contributor.advisor Frederick J. Fuller, Minor Representative, Member en_US
dc.contributor.advisor R. Julian Preston, Member en_US
dc.contributor.advisor J. Christopher Corton, Outside Consultant, Member en_US Anderson, Steven P. en_US 2010-04-02T18:56:38Z 2010-04-02T18:56:38Z 2001-11-15 en_US
dc.identifier.other etd-20011101-131940 en_US
dc.description.abstract Recognition that peroxisome proliferator chemicals are potent hepatic mitogens and carcinogens in rats and mice has generated concern about possible human health risks associated with exposure to several of these chemicals, many of which have medical or commercial utility. Our broad objective was to improve the estimation of human health risk following peroxisome proliferator exposure by defining a subset of the molecular events associated with the rodent tumors. Our working hypothesis was that peroxisome proliferator-induced tumors in rodents result from specific, peroxisome proliferator-activated receptor-a(Ppara)-modulated changes in gene expression. The research was directed toward three specific aims. First, we sought to identify genes associated with hepatocarcinogenesis induced by the peroxisome proliferator, Wy-14, 643, in the rat. The principle conclusion of these studies - that peroxisome proliferators dysregulate expression of hepatic acute-phase protein genes - suggested possible perturbations in cytokine signaling networks that also regulate cell growth. Second, although Ppara is necessary for the rodent hepatocarcinogenesis induced by peroxisome proliferators, we were interested in identifying more proximate mediators of the increased cell proliferation. Thus, we examined cytokine signaling in mice treated with peroxisome proliferators. We found that peroxisome proliferator-induced increases in cell proliferation is not mediated via Tnfasignaling, but instead may be mediated through interleukin-1b or interleukin-6. Third, because Ppara is necessary for the cell proliferation that follows peroxisome proliferator exposure, we hypothesized that the receptor may play a role in hepatocellular proliferation induced by other stimuli. Following partial hepatectomy, liver regeneration in Ppara-null mice is transiently impaired, and may result from altered expression of genes regulating the G1/S cell cycle checkpoint in hepatocytes from these mice. Overall, our studies suggest that hepatic Ppara activation (1) alters inflammatory mediators, (2) modulates several potentially mitogenic cytokines, and (3) is necessary for normal liver regeneration after partial hepatectomy. Our data, compared with data from similar experiments on human hepatocytes, may provide further clues about the differences and similarities between peroxisome proliferator exposure in humans and laboratory animals. en_US
dc.rights I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. en_US
dc.title Gene modulation during peroxisome proliferator-induced hepatocarcinogenesis en_US PhD en_US PhD Dissertation en_US Comparative Biomedical Sciences en_US

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