UW-Madison School of Pharmacy

Navigation Options

head shot image

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:
  • Marzinke MA, Mavencamp T, Duratinsky J, Clagett-Dame M.  14-3-3∈ and NAV2 interact to regulate neurite outgrowth and axon elongation.  Arch Biochem Biophys.  2013 540:94-100.
  • 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.
  • Pandey R, Zella J, Clagett-Dame M, Plum LA, DeLuca HF, Doyne DW.  A phase 2A dose ranging study of an oral calcitriol analog (2MD) in secondary hyperparathyroidism in patients on hemodialysis.  Submitted, American J of Nephrology.  2016:43:213-20.
  • McNeill EM, Klöckner-Bormann M, Roesler EC, Talton LE, Moechars D, Clagett-Dame M. Nav2 hypomorphic mutant mice are ataxic and exhibit abnormalities in cerebellar development. Dev Biol. 2011 May 15;353(2):331-43. Epub 2011 Mar 16.
  • Grzywacz P, Chiellini G, Plum LA, Clagett-Dame M, DeLuca HF. Removal of the 26-methyl group from 19-nor-1α,25-dihydroxyvitamin D3; markedly reduces in vivo calcemic activity without altering in vitro VDR binding, HL-60 cell differentiation, and transcription. J Med Chem. 2010 Dec 23;53(24):8642-9. Epub 2010 Nov 24.
  • DeLuca HF, Bedale W, Binkley N, Gallagher JC, Bolognese M, Peacock M, Aloia J, Clagett-Dame M, Plum L. The vitamin D analogue 2MD increases bone turnover but not BMD in postmenopausal women with osteopenia: results of a 1-year phase 2 double-blind, placebo-controlled, randomized clinical trial. J Bone Miner Res. 2011 Mar;26(3):538-45. doi: 10.1002/jbmr.256.
  • Li H, Palczewski K, Baehr W, Clagett-Dame M. Vitamin A deficiency results in meiotic failure and accumulation of undifferentiated spermatogonia in prepubertal mouse testis. Biol Reprod. 2011 Feb;84(2):336-41. Epub 2010 Sep 29.
  • Nieves NJ, Ahrens JM, Plum LA, DeLuca HF, Clagett-Dame M. Identification of a unique subset of 2-methylene-19-nor analogs of vitamin D with comedolytic activity in the rhino mouse. J Invest Dermatol. 2010 Oct;130(10):2359-67. Epub 2010 Jun 10.
  • McNeill EM, Roos KP, Moechars D, Clagett-Dame M. Nav2 is necessary for cranial nerve development and blood pressure regulation. Neural Dev. 2010 Feb 25;5:6.
  • Marzinke MA, Henderson EM, Yang KS, See AW, Knutson DC, Clagett-Dame M. Calmin expression in embryos and the adult brain, and its regulation by all-trans retinoic acid. Dev Dyn. 2010 Feb;239(2):610-9.
  • Li H, MacLean G, Cameron D, Clagett-Dame M, Petkovich M. Cyp26b1 expression in murine Sertoli cells is required to maintain male germ cells in an undifferentiated state during embryogenesis. PLoS One. 2009 Oct 19;4(10):e7501.
  • Barycki R, Sicinski RR, Plum LA, Grzywacz P, Clagett-Dame M, Deluca HF. Removal of the 20-methyl group from 2-methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D(3) (2MD) selectively eliminates bone calcium mobilization activity. Bioorg Med Chem. 2009 Nov 15;17(22):7658-69. Epub 2009 Sep 29.
  • Li H, Clagett-Dame M. Vitamin A deficiency blocks the initiation of meiosis of germ cells in the developing rat ovary in vivo. Biol Reprod. 2009 Nov;81(5):996-1001. Epub 2009 Jul 8.