A classical function of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is to maintain calcium homeostasis in vertebrate organisms. This activity is achieved through direct actions on intestine, kidney and bone, and feedback regulated at the parathyroid gland. 1,25(OH)2D3 also exerts additional biologic actions on a wide range of tissue types, primarily as a regulator of cell growth and differentiation. These highly pleiotropic actions suggest that 1,25(OH)2D3 or synthetic derivatives thereof may be useful therapeutically for such indications as cancer, and autoimmune and skin diseases. This utility is plagued, however, by the propensity for 1,25(OH)2D3 to hyper-induce intestinal calcium absorption, renal calcium reabsorption and bone calcium resorption. Recently, however, our understanding of these biologic processes has increased substantially, due largely to the discovery of key target genes whose products play central roles in orchestrating the homeostatic events. As a consequence, three specific aims are proposed.
Aim 1 : To determine the molecular mechanisms that underlie the regulation by 1,25(OH)2D3 of genes that are central to the calcium homeostatic actions of intestine, kidney and bone in vivo. We will use novel molecular techniques to characterize 1,25(OH)2D3`s ability to promote VDR/RXR DNA binding, coactivator interaction, chromatin modification, RNA pol II recruitment, and induction of renal TRPV5, intestinal TRPV6, and skeletal RankL gene activity in a mouse model in vivo.
Aim 2 : To evaluate the role of intracellular, vitamin D-inactivating metabolism on 1,25(OH)2D3 activity in the three primary organs. We plan to explore the consequence of Cyp24a1 inactivation on 1,25(OH)2D3`s ability to trigger TRPV5, TRPV6 and RankL activation using the Cyp24a1 null mouse.
Aim 3 : To assess the underlying mechanisms responsible for the increased biological potency and/or altered selectivity manifested by classic vitamin D analogues in vivo. We plan to characterize in vivo the mechanisms responsible for the increased potency, efficacy and selectivity for three well recognized vitamin D analogues. The research proposed herein will provide novel insight into the underlying mechanisms responsible for the calcemic activity of 1,25(OH)2D3 in vivo, define the impact of ligand pharmacodynamics on these activities and identify mechanisms whereby vitamin D analogues exert unique blends of biologic potency, efficacy and selectivity. These concepts will enable more rationale approaches to the design and synthesis of therapeutically relevant vitamin D analogues.

Public Health Relevance

Vitamin D plays significant roles both in the maintenance of mineral homeostasis and in the control of cellular growth and function. The studies herein seek to enhance our understanding of the mechanisms that underlie vitamin D action such that better and more selective medicines can be created.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073995-05
Application #
8237042
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Maruvada, Padma
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$299,894
Indirect Cost
$91,623
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Meyer, Mark B; Pike, J Wesley (2013) Corepressors (NCoR and SMRT) as well as coactivators are recruited to positively regulated 1?,25-dihydroxyvitamin D3-responsive genes. J Steroid Biochem Mol Biol 136:120-4
Lieben, Liesbet; Masuyama, Ritsuko; Torrekens, Sophie et al. (2012) Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 122:1803-15
Meyer, Mark B; Goetsch, Paul D; Pike, J Wesley (2012) VDR/RXR and TCF4/ýý-catenin cistromes in colonic cells of colorectal tumor origin: impact on c-FOS and c-MYC gene expression. Mol Endocrinol 26:37-51
Pike, J Wesley; Meyer, Mark B (2012) Regulation of mouse Cyp24a1 expression via promoter-proximal and downstream-distal enhancers highlights new concepts of 1,25-dihydroxyvitamin D(3) action. Arch Biochem Biophys 523:2-8
Pike, J Wesley; Meyer, Mark B; Bishop, Kathleen A (2012) Regulation of target gene expression by the vitamin D receptor - an update on mechanisms. Rev Endocr Metab Disord 13:45-55
Pike, J Wesley (2011) Genome-wide principles of gene regulation by the vitamin D receptor and its activating ligand. Mol Cell Endocrinol 347:3-10
Pike, J Wesley; Meyer, Mark B (2010) The vitamin D receptor: new paradigms for the regulation of gene expression by 1,25-dihydroxyvitamin D(3). Endocrinol Metab Clin North Am 39:255-69, table of contents
Meyer, Mark B; Goetsch, Paul D; Pike, J Wesley (2010) Genome-wide analysis of the VDR/RXR cistrome in osteoblast cells provides new mechanistic insight into the actions of the vitamin D hormone. J Steroid Biochem Mol Biol 121:136-41
Pike, J Wesley; Meyer, Mark B; Martowicz, Melissa L et al. (2010) Emerging regulatory paradigms for control of gene expression by 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol 121:130-5
Zella, Lee A; Meyer, Mark B; Nerenz, Robert D et al. (2009) The enhanced hypercalcemic response to 20-epi-1,25-dihydroxyvitamin D3 results from a selective and prolonged induction of intestinal calcium-regulating genes. Endocrinology 150:3448-56

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