UW-Madison School of Pharmacy

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Margaret Clagett-Dame, PhD

Professor


 

 

 


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.

Background: Dr. Clagett-Dame holds joint appointments in the Pharmaceutical Sciences Division and in the Department of Biochemistry. She received BS (1975) and MS (1977) degrees in nutrition from the Pennsylvania State University and a PhD 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.

Professional Interests: Neuropharmacology, biochemistry, developmental biology

Education:

  • BS 1975 Nutrition - Pennsylvania State University
  • MS 1977 Nutrition - Pennsylvania State University
  • PhD 1985 Biochemistry - University of Wisconsin-Madison
Highlighted Publications:
  • Ahrens JM, Jones JD, Nieves NJ, Mitzey AM, DeLuca HF, Clagett-Dame M. Differential activity of 2-methylene-19-nor vitamin D analogs on growth factor gene expression in rhino mouse skin and comparison to all-trans retinoic acid. PLoS One. 2017 Nov 28;12(11):e0188887. doi: 10.1371/journal.pone.0188887. eCollection 2017.
  • Pandey R, Zella JB, Zhu JG, Plum LA, Clagett-Dame M, Blaser WJ, Bedale W, DeLuca HF, Coyne DW. Pharmacokinetics of a New Oral Vitamin D Receptor Activator (2-Methylene-19-Nor-(20S)-1α,25-Dihydroxyvitamin D3) in Patients with Chronic Kidney Disease and Secondary Hyperparathyroidism on Hemodialysis. Drugs R D. 2017 Dec;17(4):597-605. doi: 10.1007/s40268-017-0210-z.
  • Thadhani R, Zella JB, Knutson DC, Blaser WJ, Plum LA, Clagett-Dame M, Buck RD, DeLuca HF. 2MD (DP001), a Single Agent in the Management of Hemodialysis Patients: A Randomized Trial. Am J Nephrol. 2017;45(1):40-48.
  • Pandey R, Zella J, Clagett-Dame M, Plum LA, DeLuca HF, Coyne DW. Use of 2MD, a Novel Oral Calcitriol Analog, in Hemodialysis Patients with Secondary Hyperparathyroidism. Am J Nephrol. 2016;43(3):213-20.
  • Cavanaugh KR, Narayanasamy S, Walker JR, Clagett-Dame M, Curley RW Jr. Improved Synthesis of the C-Glucuronide/Glycoside of 4-Hydroxybenzylretinone (4-HBR).  J Carbohydr Chem. 2016; 35(5):249-260.
  • Knutson DC, Mitzey, AM, Talton LE, Clagett-Dame M. Mice null for NEDD9 (HEF1) display extensive hippocampal dendritic spine loss and cognitive impairment. Brain Res. 2016; 1632:141-55.
  • Knutson DC, Clagett-Dame M. A complex RARE is required for the majority of Nedd9 embryonic expression. Transgenic Res. 2015; 24:123-34.
  • Chiellini G, Grzywacz P, Plum LA, Clagett-Dame M, DeLuca HF. 26-Desmethyl-2-methylene-22-ene-19-nor-1α,25-dihydroxyvitamin D3 compounds selectively active on intestine. Steroids. 2014; 83:27-38.
  • Zella JB, Plum LA, Plowchalk DR, Potochoiba M, Clagett-Dame M, DeLuca HF. Novel, selective vitamin D analog suppresses parathyroid hormone in uremic animals and postmenopausal women. Am J Nephrol. 2014; 39:476-83.
  • Grzywacz P, Plum LA, Clagett-Dame M, DeLuca HF. 26-and 27 Methyl groups of 2-substituted, 19-nor-1a,25-dihydroxylated vitamin D compounds are essential for calcium mobilization in vivo. Bioorg Chem. 2013; 47:9-16.
  • Marzinke MA, Mavencamp T, Duratinsky J, Clagett-Dame M. 14-3-3eand NAV2 interact to regulate neurite outgrowth and axon elongation. Arch Biochem Biophys. 2013 540:94-100.