Through the study of acquired and inherited hypophosphatemic disorders a new understanding of the hormonal regulators of phosphate homeostasis is emerging. FGF-23 plays a central role in the pathophysiology of several forms of hypophosphatemic rickets including tumor-induced osteomalacia (TIO), X-linked hypophosphatemic rickets (XLH) and autsomal dominant hypophosphatemic rickets (ADHR). However, the mechanism of by which this potent inhibitor of proximal renal tubular phosphate transport modulates the main hormone-responsive sodium-dependent phosphate transporter (NaPi-lla) is virtually unexplored. We hypothesize that FGF-23 inhibits sodium-dependent phosphate transport by promoting internalization of NaPi-lla via activation of FGF receptors. Furthermore, internalization is accomplished by the assembly of a macromolecular complex involving NaPi-lla and signaling molecules on the scaffold of Sodium hydrogen ion exchanger related factor-1 (NHERF-1) that interacts with the actin cytoskeleton.
In Specific Aim 1, we will determine if FGF-23 acts via known FGFRs to promote NaPi-lla internalization. We will further define the major signaling pathway(s) responsible for NaPi-lla trafficking.
In Specific Aim 2, we will examine role of NHERF-1 in FGF-23 mediated internalization of NaPi-lla.
In Specific Aim 3, we will identify NHERF-1 binding partners which serve to integrate FGF-23 signaling and NaPi-lla internalization. The experiments outlined in this proposal will establish the mechanism by which FGF-23 regulates phosphate handling in the proximal renal tubule including control of NaPi-lla trafficking, activation of the cell signaling pathways and the assembly of NHERF-1 dependent multiprotein complexes that integrate signaling and NaPi-lla membrane localization. A better understanding of FGF-23 signaling and its consequences for renal phosphate handling and ultimately skeletal mineralization will provide new therapeutic targets for disorders of phosphate homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK073273-02S1
Application #
7783360
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Mullins, Christopher V
Project Start
2007-07-01
Project End
2012-04-30
Budget Start
2008-07-01
Budget End
2009-04-30
Support Year
2
Fiscal Year
2009
Total Cost
$820
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218