This NIH mentored Career Development Award proposal describes a five year training program for the development of an academic career of a physician scientist and to facilitate the transition to an independent investigator. To accomplish these goals, the candidate and her mentors have developed an integrated plan including innovative scientific ideas, advanced training in the field of basic science research and a detailed career development plan. This research will focus on elucidating FGF23 causes decreased phosphate reabsorption from the kidney by decreasing the expression of phosphate transporter in the proximal tubule. In addition, FGF23 decreases synthesis of 1,25 vitamin D in the proximal tubule. The receptors responsible for these different actions of FGF23 are unknown. It is known that the FGF family members bind to four fibroblast growth factor receptors (FGFRs) designated as FGFR1-4. FGFR1, FGFR3 and FGFR4 are present in the proximal tubule where the majority of phosphorus is reabsorbed. A recent in vivo study using FGFR null mice indicates that FGFR1 is the predominant receptor with FGFR4 playing a minor role in regulating the phosphate transporters in the proximal tubule, but baseline phosphate homeostasis remains normal in these FGFR null mice. This grant proposes that compensatory mechanisms exist at baseline in individual FGFR-/- mice and FGFR1-/-FGFR4-/- double mutant mice will have high serum phosphate levels at baseline and have resistance to FGF23. To test this hypothesis, FGFR1-/-FGFR4-/- mice will be generated and characterized, and the effects of FGF23 will be examined. Regulation of 1,25 vitamin D appears to be different from the regulation of sodium phosphate cotransporters with individual FGFR null mice showing significant decrease in the serum levels of 1,25 vitamin D on exposure to pharmacological doses of FGF23. To study the regulation of 1,25 vitamin D, different combinations of FGFR null mice will be examined for the effects of FGF23 on serum levels of 1,25 vitamin D. This grant also hypothesizes that Klotho, an essential co-factor for the actions of FGF23 can act as an independent phosphate regulating hormone, and it interacts with FGFRs to regulate phosphate homeostasis. To test this hypothesis, the effects of Klotho on phosphate homoeostasis will be studied in the various FGFR null mice. In humans, high FGF23 levels result in disturbances in phosphate homeostasis with hypophosphatemia and low 1,25 Vitamin D levels resulting in rickets, bone fractures and poor growth. High levels of FGF23 have also been associated with increased risk of mortality in patients with chronic kidney disease. Identifying the receptors for FGF23 will provide insights in to the mechanisms of actions of FGF23 and provide foundation for designing novel therapies to prevent the effects of FGF23.

Public Health Relevance

Patients with high levels of FGF23 have rickets, poor growth, and increased risk of fractures, and lack curative therapy. The current therapy results in kidney stones and progressive renal injury. The identification of specific receptors for FGF23 will help in designing specific receptor antagonists and thus provide curative treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK089295-04
Application #
8537442
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M2))
Program Officer
Rankin, Tracy L
Project Start
2010-09-15
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$145,195
Indirect Cost
$10,755
Name
University of Texas Sw Medical Center Dallas
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Gattineni, Jyothsna; Alphonse, Priyatharshini; Zhang, Qiuyu et al. (2014) Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am J Physiol Renal Physiol 306:F351-8
Gattineni, Jyothsna (2014) Inherited disorders of calcium and phosphate metabolism. Curr Opin Pediatr 26:215-22
Joseph, Catherine; Gattineni, Jyothsna (2013) Complement disorders and hemolytic uremic syndrome. Curr Opin Pediatr 25:209-15
Gattineni, Jyothsna; Twombley, Katherine; Goetz, Regina et al. (2011) Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4. Am J Physiol Renal Physiol 301:F371-7