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 is designed to characterize basal and hormone-stimulated regulation of the human and murine NaPi-lIb genes. The second aim is 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 is 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.