Postdoctoral work, National Cancer Institute, 1995-99

Postdoctoral work, Institute of Toxicology and Environmental Health, University of California, Davis, 1992-95

Ph.D., Nutrition Science, University of California, Davis, 1992

B.S. Dietetics, University of California, Davis, 1985

Our laboratory studies the roles of the peroxisome proliferator-activated receptors (PPARs) in the regulation of homeostasis, toxicology, and carcinogenesis with extensive application of null mouse models. PPARs are members of the nuclear receptor superfamily and are critical modulators of environmental and dietary stimuli. Acting as regulatory transcription factors, the PPARs modulate gene expres-sion of target genes containing peroxisome proliferator responsive elements in response to ligand activation. Activation of the PPARa can occur as a result of cold shock, food restriction, dietary fatty acids, and treatment with the hypolipidemic fibrate class of drugs. Numerous genes that modulate lipid metabolism are regulated by PPARa and PPARg ligands/activators. Our understanding of PPAR function has been greatly enhanced from null mouse models. Data obtained from these models provide strong in vivo evidence that the PPARa and PPARg regulate lipid metabolism by regulating gene expression of numerous proteins that are clinically relevant for a number of diseases including diabetes, obesity, artherosclerosis, and cancer. The function of the PPARb(d) has remained elusive. While the PPARb is ubiquitously expressed, some tissues express relatively higher levels of the mRNA, including the brain, adipose, and epithelium. No target genes have been identified that are controlled only by the PPARb. There are several reports suggesting roles for PPARb in lipid metabolism, epidermal cell function, and colon cancer. We are using the PPARb-null mouse model that I made at the National Cancer Institute to elucidate the biological functions of the PPARb.

The best model described to date to study the role of the PPARb are epithelial cells. PPARb expression is increased significantly in epithelium including (a) skin in response to administration of the tumor promoter TPA and (b) colon cells as a result of inactivation of the APC locus. These are the first two models to show modulation of PPARb expression and suggest a role for the PPARb in epithelial cell tumor forma-tion. Further, there is evidence that the non-steroidal anti-inflammatory drug (NSAID) sulindac may prevent tumor formation by interacting with the PPARb. Since sulindac and other NSAIDs are reported to have anti-cancer benefits by altering either cell proliferation, apoptosis or both, delineating the precise role of this drug in epithelial cell-related carcinomas is of great interest. Part of our research is directed at both skin and colon as models to investigate to the role of PPARb in epithelial cells. Our laboratory in collabora-tion with investigators at the National Cancer Institute, Johns Hopkins University and the University of California, San Francisco, is investigating how the PPARb contributes to epithelial carcinogenesis using several approaches including genetic and chemically induced cancer models. Additionally, the influence of NSAIDs in these model systems is under investigation. The goal of this research is to identify functional roles of the PPARb in the epithelial cell function as well as the etiology and prevention of epithelial carcinogenesis.

A second related research area being developed in our laboratory is delineating the role of the PPARb in the regulation of homeostasis including body composition, tissue specific gene expression, serum lipid biochemistry, and artherosclerosis. Results from this research will determine if the PPARb regulates physiological lipid metabolism using different activators reported to interact through the PPARb.

Kim, D.J., Bility, M.T., Billin, A.N., Willson, T.M., Gonzalez, F.J. and Peters, J.M .. Peroxisome proliferator-activated receptor- b/d selectively induces differentiation and inhibits cell proliferation. Cell Death and Differentiation (2005) In Press.

Burdick, A.D., Kim, D.J., Peraza, M.A., Gonzalez, F.J. and Peters, J.M .. The role of peroxisome proliferator-activated receptor- b/d in epithelial cell growth and differentiation. Cellular Signaling (2005) In Press.

Kim, D.J., Murray, I., Burns, A.M., Gonzalez, F.J., Perdew, G.H. and Peters, J.M . Peroxisome proliferator-activated receptor- b (PPAR b ) attenuates epidermal cell proliferation via ubiquitin-dependent down-regulation of kinase activity. The Journal of Biological Chemistry (2005) 280:9519-9527.

Hays, T., Rusyn, I. , Burns, A.M., Gonzalez, F.J., Kennett, M.J., Ward, J.M. and Peters, J.M .. Role of the peroxisome proliferator-activated receptor a (PPAR a ) in bezafibrate-induced hepatocarcinogenesis. Carcinogenesis (2005) 26:219-227.

Harman, F., Nicol, C.J., Marin, H.E., Ward, J.M., Gonzalez, F.J. and Peters. J.M . Peroxisome proliferator-activated receptor- d/b (PPAR d/b ) attenuates colon carcinogenesis. Nature Medicine (2004) 10:481-483.

Kim, D.J., Akiyama, T. E., Harman, F., Burns, A.M., Shan, W., Ward, J.M., Kennett, M.J., Gonzalez, F.J. and Peters, J.M . PPAR b(d )-dependent regulation of ubiquitin C expression contributes to attenuation of skin carcinogenesis. The Journal of Biological Chemistry (2004) 279:23719-23727.

Bility, M.T., Thompson, J., McKee, R.H., David, R.M., Butala, J.H., Vanden Heuvel, J.V. and Peters, J.M .. Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters. Toxicological Sciences (2004) 82:170-182.

Akiyama, T., Nicol, C.J., Fievet, C., Staels, B., Ward, J.M., Gonzalez, F.J., Auwerx, J. and Peters, J.M .. Peroxisome proliferator-activated receptor- a (PPAR a ) regulates lipid homeostasis but is not associated with obesity: Studies with congenic mouse lines. The Journal of Biological Chemistry (2001) 276:39088-39093.

Peters, J.M ., Lee, S.S.T., Li, W., Ward, J.M., Gavrilova, O., Everett , C., Reitman, M.L., Hudson , L.D. and Gonzalez, F.J.. Growth, adipose, brain and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor b(d ). Molecular and Cellular Biology (2000) 20:5119-5128.