The active form of vitamin D (1,25(OH)2D) regulates events in bone, kidney and intestine to control whole body Ca metabolism and influence the development of osteroporosis. Several lines of evidence suggest that the role of Ca absorption in osteoporosis development requires additional attention: Ca absorption efficiency is reduced with aging and in post-menopausal women with fractures;low fractional Ca absorption has been associated with increased hip fracture risk in post-menopausal women, and intestinal resistance to the action of 1,25(OH)2 D develops in the elderly and in post-menopausal women. The long-term goal of my research is to understand the cellular mechanisms causing low fractional Ca absorption and reduced intestinal vitamin D action that contribute to osteoporosis. Many aspects of the models proposed to explain vitamin D-regulated Ca absorption have not been tested. This proposal reflects the evolution of our mechanistic understanding of vitamin D action in the enterocyte and our interest in translating fundamental research findings into the complex physiology of whole body Ca metabolism.
Our specific aims are: (1) To assess the importance of VDR location and level in the control of intestinal Ca absorption. We will use genetically modified mice to test if high intestinal VDR can prevent age-associated calcium malabsorption and intestinal vitamin D resistance (subaim1a) and we will determine whether the deletion of VDR specifically from the ileum, cecum, and colon can alter whole body calcium metabolism (subaim1b), (2) To determine whether the apical membrane Ca channel TRPV6 is essential for intestinal Ca uptake and absorption. We will use genetically modified mice to determine whether intestinal TRPV6 can recover the VDR null phenotype and prevent loss of Ca absorption with aging, (3) To determine the factors controlling vitamin D-mediated gene activation in enterocytes. We will conduct cell and animal studies to determine the active role RXR1 has in VDR mediated gene transcription (subaim 3a) and cell studies to assess the role that intranuclear VDR movement and promoter on-off kinetics plays in vitamin D-mediated gene transcription (subaim 3b). We are uniquely positioned to test these hypotheses and to expand our understanding of how vitamin D regulated Ca absorption helps protect bone health. Our work will provide preclinical evidence for strategies to optimize Ca absorption and prevent osteoporosis.

Public Health Relevance

Dietary calcium is essential for bone health and the prevention of the bone disease osteoporosis. Unfortunately, the ability of the intestine to absorb dietary calcium is reduced with aging and the menopause. Vitamin D is the major regulator of intestinal calcium absorption but many factors may impair vitamin D action. We will conduct mechanistic and translational studies to examine how vitamin D influences intestinal calcium absorption. Our focus will be on events that occur through a protein that binds vitamin D, the vitamin D receptor. This work will lay the foundation for developing osteoporosis prevention strategies that maximize vitamin D action in the intestine and optimize the absorption of dietary calcium.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-M (02))
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Grey, Michael J
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Purdue University
Other Domestic Higher Education
West Lafayette
United States
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Fleet, James C (2017) The role of vitamin D in the endocrinology controlling calcium homeostasis. Mol Cell Endocrinol 453:36-45
DeSmet, Marsha L; Fleet, James C (2017) Constitutively active RAS signaling reduces 1,25 dihydroxyvitamin D-mediated gene transcription in intestinal epithelial cells by reducing vitamin D receptor expression. J Steroid Biochem Mol Biol 173:194-201
Reyes Fernandez, Perla C; Replogle, Rebecca A; Wang, Libo et al. (2016) Novel Genetic Loci Control Calcium Absorption and Femur Bone Mass as Well as Their Response to Low Calcium Intake in Male BXD Recombinant Inbred Mice. J Bone Miner Res 31:994-1002
Reyes-Fernandez, Perla C; Fleet, James C (2016) Compensatory Changes in Calcium Metabolism Accompany the Loss of Vitamin D Receptor (VDR) From the Distal Intestine and Kidney of Mice. J Bone Miner Res 31:143-51
Reyes-Fernandez, Perla C; Fleet, James C (2015) Luminal glucose does not enhance active intestinal calcium absorption in mice: evidence against a role for Ca(v)1.3 as a mediator of calcium uptake during absorption. Nutr Res 35:1009-15
Cui, Min; Li, Qiang; Johnson, Robert et al. (2012) Villin promoter-mediated transgenic expression of transient receptor potential cation channel, subfamily V, member 6 (TRPV6) increases intestinal calcium absorption in wild-type and vitamin D receptor knockout mice. J Bone Miner Res 27:2097-107
Jiang, Yan; Fleet, James C (2012) Effect of phorbol 12-myristate 13-acetate activated signaling pathways on 1?, 25 dihydroxyvitamin D3 regulated human 25-hydroxyvitamin D3 24-hydroxylase gene expression in differentiated Caco-2 cells. J Cell Biochem 113:1599-607
Jiang, Yan; Fleet, James C (2012) Phorbol esters enhance 1?,25-dihydroxyvitamin D3-regulated 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) gene expression through ERK-mediated phosphorylation of specific protein 3 (Sp3) in Caco-2 cells. Mol Cell Endocrinol 361:31-9
Farrow, Emily G; Yu, Xijie; Summers, Lelia J et al. (2011) Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A 108:E1146-55
Adamec, Jiri; Jannasch, Amber; Huang, Jianjie et al. (2011) Development and optimization of an LC-MS/MS-based method for simultaneous quantification of vitamin D2 , vitamin D3 , 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3. J Sep Sci 34:11-20

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