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 RXR? 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 bindings 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054111-14
Application #
8204977
Study Section
Special Emphasis Panel (ZRG1-EMNR-M (02))
Program Officer
Grey, Michael J
Project Start
1997-09-15
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
14
Fiscal Year
2012
Total Cost
$317,864
Indirect Cost
$104,692
Name
Purdue University
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
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
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Verzi, Michael P; Shin, Hyunjin; He, H Hansen et al. (2010) Differentiation-specific histone modifications reveal dynamic chromatin interactions and partners for the intestinal transcription factor CDX2. Dev Cell 19:713-26
Saddoris, Kari L; Fleet, James C; Radcliffe, John S (2010) Sodium-dependent phosphate uptake in the jejunum is post-transcriptionally regulated in pigs fed a low-phosphorus diet and is independent of dietary calcium concentration. J Nutr 140:731-6
Xue, Yingben; Fleet, James C (2009) Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology 136:1317-27, e1-2
Cui, Min; Klopot, Anna; Jiang, Yan et al. (2009) The effect of differentiation on 1,25 dihydroxyvitamin D-mediated gene expression in the enterocyte-like cell line, Caco-2. J Cell Physiol 218:113-21

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