Ph.D., 1975, Pennsylvania State University, The Milton S. Hershey College of Medicine
Mechanisms of Gene Induction by Peroxisome Proliferators
Dr. Geoghegan's lab is studying the effects of DHEA on gene expression. DHEA is a precursor for the gonadal steroids, but has independent effects as a modulator of gene expression. Dr. Geoghegan collaborates with Dr. Russ Prough who has demonstrated that DHEA is a peroxisome proliferator in rodents. Peroxisome proliferation involves induction of a number of genes associated with peroxisomal fatty acid oxidation as well as microsomal P450s involved in omega hydroxylation of fatty acids. These effects are mediated by activation of PPAR-alpha, a member of the nuclear hormone superfamily of transcription factors. We have also demonstrated that DHEA induces expression of cytochrome P450 3A, a major inducible drug metabolizing enzyme in the liver. This occurs by mechanisms that appear to be independent of PPAR. Using gene array analysis we have recently identified a number of other novel genes whose expression is affected in the liver by treatment with DHEA. Ultimately, identification of these genes and an understanding of how they are regulated , will help to elucidate the myriad physiological and biochemical affects associated with DHEA.
Webb SJ, Geoghegan TE, Prough RA, Michael Miller KK. (2006)The biological actions of dehydroepiandrosterone involves multiple receptors. Drug Metab Rev. 2006;38(1-2):89-116. Review.
S Gu, SL Ripp, RA Prough, and TE Geoghegan. Dehydroepiandrosterone Affects theExpression of Multiple Genes in Rat Liver Including 11b–Hydroxysteroid Dehydrogenase Type I: A cDNA Array Analysis. Mol. Pharm. 63, 722-731, (2003).
Parimal Bhattacherjee, P Mukhopadhyay, SL Tilley, BH Koller, T.Geoghgan and CA Paterson. Blood-Aqueous Barrier in Prostaglandin EP2 Receptor Knockout Mice. J. Ocular Immunology and Inflamation.10; 187-96 (2002)
Regulation of the rat glutathione S-transferase A2 gene by glucocorticoids: involvement of both the glucocorticoid and pregnane X receptors. Cameron K. Falkner, J.A. Pinaire, G-H. Xiao, T.E. Geoghegan and R.A. Prough.(2001) Mol. Pharm. 60, 611-619.
Cytochrome P-450 mRNAs are modulated by dehydroepiandrosterone, nafenopin, and triiodothyronine. Singleton DW, Lei XD, Webb SJ, Prough RA, Geoghegan TE. (1999) Drug Metab Dispos. 27:193-200.
Expression of prostaglandin receptors EP4 and FP in human lens epithelial cells. (1999). Mukhopadhyay P, Bhattacherjee P, Andom T, Geoghegan TE, Andley UP, Paterson CA. Invest Ophthalmol Vis Sci 1999 Jan;40(1):105-12.
Detection of EP2, EP4, and FP Receptors in Human Ciliary Epithelial and Ciliary Muscle Cells. (1997). Mukhopadhyay, P., T. E. Geoghegan, R. V. Patil, P. Bhattacherjee and C.A. Paterson. Biochemical Pharmacology 53: 1249-1255.
Regulation of CTP4A Expression in Rat by Dehydroepiandrosterone and Thyroid Hormone. (1996). S.J. Webb, G.-H. Xiao, T. E. Geoghegan, and R.A. Prough. Molecular Pharmacology 49, 276-287.
Regulation of Cytochromes P450 by DHEA and Its Anticarcinogenic Action. Prough, R.A., X.-D. Lei, G.-H. Xiao, H.-Q. Wu, T. E. Geoghegan, and S.J. Webb (1995) Ann New York Acad Sci 774, 187-199.