Research Areas:

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 stimulii. Acting as regulatory transcription factors, the PPARs modulate gene expression 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 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 formation. 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 collaboration with investigators at the National Cancer Institute, Johns Hopkins University and the University of California at 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.

"Role of the PPARb in epithelial cell proliferation", National Institutes of Health, R01CA89607.

"Role of the PPARb in colon carcinogenesis", National Institute of Health, R01CA97999.

Representative Publications

Lab Pictures

PPAR Resource Page                                   

Laboratory of Metabolism

Last Updated April 26, 2005 by Michael Borland