Abstract

This is a competing renewal application of a MERIT Award designed to continue studies in intestinal phosphate absorption at the physiological and molecular levels. These studies will test the hypothesis that intestinal phosphate absorption involves proteins encoded by sodium phosphate-lIb (NaPi-lIb), sodium phosphate-Ill (NaPi-III), and Phosphate encoding gene with Homologies to Endopeptidases on the X chromosome (PHEX) genes. Understanding the regulation of these key genes will provide valuable insight into the overall phosphate homeostasis. The studies will utilize state-of-the-art in vivo and in vitro experiments that are designed to gain further information on the regulation and interrelationship between NaPi-llb, NaPi-Ill, and PHEX genes in relationship to bone health during maturation. We have been exceedingly productive during the last funding period with significant advances being made in cloning the NaPi-Ilb, NaPi-lil, and the promoter region for both the phosphate transporters and the PHEX promoter. The current studies are designed to address four specific aims.
The first aim i s designed to characterize basal and hormone-stimulated regulation of the human and murine NaPi-lIb genes.
The second aim i s designed to decipher the basal and vitamin D3-stimulated transcriptional regulation of the murine NaPi-Ill gene.
Specific Aim 3 is designed to determine if fibroblast growth factor-23 (FGF-23) is a possible PHEX substrate which is involved in the regulation of intestinal phosphate absorption.
Specific Aim 4 is designed to utilize a novel proteomic approach to search for putative PHEX substrate and for downstream targets in the intestinal epithelium.
The final aim i s designed to investigate basal and glucocorticoid-mediated transcriptional regulation of the murine PHEX gene. These studies will likely yield significant new information in regard to these important genes which are involved in the phosphate homeostasis. These studies will allow us to develop newer approaches to the treatment of bone disorders during maturation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK033209-21
Application #
6542022
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (01))
Program Officer
May, Michael K
Project Start
1983-12-01
Project End
2007-11-30
Budget Start
2003-03-15
Budget End
2003-11-30
Support Year
21
Fiscal Year
2003
Total Cost
$356,025
Indirect Cost

  Institution

Name
University of Arizona
Department
Pediatrics
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721

  Publications

Ghishan, Fayez K; Kiela, Pawel R (2017) Vitamins and Minerals in Inflammatory Bowel Disease. Gastroenterol Clin North Am 46:797-808
Radhakrishnan, Vijayababu M; Ramalingam, Rajalakshmy; Larmonier, Claire B et al. (2013) Post-translational loss of renal TRPV5 calcium channel expression, Ca(2+) wasting, and bone loss in experimental colitis. Gastroenterology 145:613-24
Chen, Huacong; Xu, Hua; Dong, Jiali et al. (2009) Tumor necrosis factor-alpha impairs intestinal phosphate absorption in colitis. Am J Physiol Gastrointest Liver Physiol 296:G775-81
Kiela, Pawel R; Ghishan, Fayez K (2009) Ion transport in the intestine. Curr Opin Gastroenterol 25:87-91
Li, Tao; Bai, Liqun; Li, Jing et al. (2008) Sp1 is required for glucose-induced transcriptional regulation of mouse vesicular glutamate transporter 2 gene. Gastroenterology 134:1994-2003
Barthel, Thomas K; Mathern, Douglas R; Whitfield, G Kerr et al. (2007) 1,25-Dihydroxyvitamin D3/VDR-mediated induction of FGF23 as well as transcriptional control of other bone anabolic and catabolic genes that orchestrate the regulation of phosphate and calcium mineral metabolism. J Steroid Biochem Mol Biol 103:381-8
Uno, Jennifer K; Kolek, Olga I; Hines, Eric R et al. (2006) The role of tumor necrosis factor alpha in down-regulation of osteoblast Phex gene expression in experimental murine colitis. Gastroenterology 131:497-509
Xu, Hua; Uno, Jennifer K; Inouye, Michael et al. (2005) NF1 transcriptional factor(s) is required for basal promoter activation of the human intestinal NaPi-IIb cotransporter gene. Am J Physiol Gastrointest Liver Physiol 288:G175-81
Kolek, Olga I; Hines, Eric R; Jones, Marci D et al. (2005) 1alpha,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 289:G1036-42
Li, Tao; Ghishan, Fayez-K; Bai, Liqun (2005) Molecular physiology of vesicular glutamate transporters in the digestive system. World J Gastroenterol 11:1731-6

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