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Education:

• B.S. 1975 Nutrition Pennsylvania State University
• M.S. 1977 Nutrition Pennsylvania State University
• Ph.D. 1985 Biochemistry University of Wisconsin-Madison

Overview

Dr. Clagett-Dame holds joint appointments in the Pharmaceutical Sciences Division and in the Department of Biochemistry. She received B.S. (1975) and M.S. (1977) degrees in nutrition from the Pennsylvania State University and a Ph.D. degree (1985) in biochemistry from the University of Wisconsin-Madison. Dr. Clagett-Dame worked as a biochemist in the Neuroscience Research Division at Abbott Laboratories (1986-1989) before joining the School of Pharmacy faculty. Her research interests are in neuropharmacology.

The Clagett-Dame lab studies the molecular mechanism of action and therapeutic uses of retinoids (vitamin A-like compounds) and vitamin D analogs. Retinoid analogs are being studied for the treatment of mammary cancer and neuroblastoma, and the use of vitamin analogs for the treatment of acne and obesity are also under study. A second major area of research in the lab involves understanding the molecular mechanism of action of the vitamin A metabolite, all-trans retinoic acid (RA), during embryogenesis, with particular emphasis on the developing nervous system.

Both retinoids and 1,25-dihydroxyvitamin D analogs act by binding to nuclear receptors. These receptors function as ligand-activated transcription factors that modulate gene transcription. Both of these classes of compounds are used therapeutically in the fields of dermatology and show promise in the field of oncology. However, toxicity is experienced at pharmacological concentrations. Before the therapeutic potential of these vitamin analogs can be fully realized, it will be necessary to understand how they function normally at the cellular and molecular level and how function is disrupted in toxicity.

Recently, we have discovered a series of modified retinoid analogs, including the 4-HPR analog 4hydroxybenzylretinone, that are highly effective anticancer agents but are much less toxic than many natural retinoids. These analogs do not appear to bind to the nuclear retinoid receptors to produce their activity. We are currently studying the mechanism of action of these novel retinoids.

A final focus of the lab has been the delineation of retinoid-responsive genes whose expression is altered in retinoid deficiency or excess and to establish how these changes lead to an abnormal phenotype. The lab uses cell culture, animal models of vitamin deficiency, as well as genetic mouse models in order to understand how the vitamin and its active metabolites act.

Work-Related Interests/Research:

Neuropharmacology, biochemistry, developmental biology

Highlighted Publications:

• Plum LA, Fitzpatrick LA, Ma X, Bindley NC, Zella JB, Clagett-Dame M, DeLuca HF. 2MD, a new analbolic agent for osteoporosis treatment. Osteoporosis International 2006; 17:704-715.
• Clagett-Dame M, McNeill EM, Muley PD. The role of all-trans retinoic acid in neurite outgrowth and axonal elongation. J Neurobiology 2006; 66:739-756.
• Alshafie GA, Walker JR, Curley RW, Clagett-Dame M, Highland MA, Nieves NJ, Stonerock LA and Abou-Issa H. Inhibition of mammary tumor growth by a novel nontoxic retinoid: Chemotherapeutic evaluation of a C-linked analog of 4-HPR-glucuronide. Anticancer Res 2005; 25:2391-2398.
• Merrill RA, Ahrens JM, Kaiser ME, Federhart KS, Poon VY, Clagett-Dame M. All-trans retinoic acid-responsive genes identified in the human SH-SY5Y neuroblatoma cell line and their regulated expression in the nervous system of early embryos. Biol Chem 2004; 385: 605-614.