The long term objectives are to establish expertise in metabolic bone research, to characterize the regulation of fibroblast growth factor-23 (FGF23) across the age spectrum of children, and to to explore the pathophysiology of this hormone in phosphate wasting disorders in order to optimize treatment for these disorders. FGF23 is a key regulator of phosphate and vitamin D metabolism, and FGF23 dysregulation is central to X-linked hypophosphatemic rickets (XLH). Serum phosphate concentrations are higher in children than in adults, which may be FGF23 mediated. There is little knowledge concerning the impact of FGF23 on phosphate and skeletal metabolism in healthy children, the effect of treatment of XLH with calcitriol and phosphate on FGF23, or the impact of FGF23 on adverse outcomes of XLH therapy. This lack of knowledge is detrimental to the safety of therapy for XLH. The overall hypothesis is that FGF23 is important in normal phosphate homeostasis in growing children and that FGF23 dysregulation is critical to phosphate wasting syndromes. We hypothesize that FGF23 concentrations vary with age, race, and sex during childhood and are related to parameters of phosphate metabolism and bone mineral content (Aim 1). We will measure serum FGF23, and blood and urine biochemistries on stored samples from healthy black and white boys and girls between the ages of 0 and 16 years (with bone mineral content assessment in a subset). To test the hypothesis that FGF23 levels in XLH are affected by treatment with calcitriol and phosphate and predict disease outcomes (Aim 2), we will enroll subjects with XLH in a prospective study, measuring serial FGF23 concentrations along with clinically important outcomes of XLH treatment, including the major side effects of therapy. These studies will lead to improvements in therapy for XLH. This award will allow the principal investigator to pursue clinical research in a strong mentored environment, while engaging in didactic coursework and specialized training in bone-specific research techniques (including bone histomorphometry and quantitative computed tomography), enhancing his future success as an independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AR057096-04
Application #
8289355
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Chen, Faye H
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$128,526
Indirect Cost
$8,262
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Imel, Erik A; Gray, Amie K; Padgett, Leah R et al. (2014) Iron and fibroblast growth factor 23 in X-linked hypophosphatemia. Bone 60:87-92
Lee, Janet Y; Imel, Erik A (2013) The changing face of hypophosphatemic disorders in the FGF-23 era. Pediatr Endocrinol Rev 10 Suppl 2:367-79
Imel, Erik A; Econs, Michael J (2012) Approach to the hypophosphatemic patient. J Clin Endocrinol Metab 97:696-706
Carpenter, Thomas O; Imel, Erik A; Holm, Ingrid A et al. (2011) A clinician's guide to X-linked hypophosphatemia. J Bone Miner Res 26:1381-8
Farrow, Emily G; Imel, Erik A; White, Kenneth E (2011) Miscellaneous non-inflammatory musculoskeletal conditions. Hyperphosphatemic familial tumoral calcinosis (FGF23, GALNT3 and ?Klotho). Best Pract Res Clin Rheumatol 25:735-47
Imel, Erik A; Peacock, Munro; Gray, Amie K et al. (2011) Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab 96:3541-9
Imel, Erik A; DiMeglio, Linda A; Hui, Siu L et al. (2010) Treatment of X-linked hypophosphatemia with calcitriol and phosphate increases circulating fibroblast growth factor 23 concentrations. J Clin Endocrinol Metab 95:1846-50