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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Sharrock, William J
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Robinson-Cohen, Cassianne; Bartz, Traci M; Lai, Dongbing et al. (2018) Genetic Variants Associated with Circulating Fibroblast Growth Factor 23. J Am Soc Nephrol 29:2583-2592
Imel, Erik A; Liu, Ziyue; McQueen, Amie K et al. (2016) Serum fibroblast growth factor 23, serum iron and bone mineral density in premenopausal women. Bone 86:98-105
Koller, Daniel L; Imel, Erik A; Lai, Dongbing et al. (2016) Genome-wide association study of serum iron phenotypes in premenopausal women of European descent. Blood Cells Mol Dis 57:50-3
Fisher, Marisa M; Cabrera, Susanne M; Imel, Erik A (2015) Successful treatment of neonatal severe hyperparathyroidism with cinacalcet in two patients. Endocrinol Diabetes Metab Case Rep 2015:150040
Suvannasankha, Attaya; Tompkins, Douglas R; Edwards, Daniel F et al. (2015) FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells. Oncotarget 6:19647-60
Keskar, Vaibhav S; Imel, Erik A; Kulkarni, Manjunath et al. (2015) The Case | Ectopic calcifications in a child. Kidney Int 87:1079-81
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
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

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