FGF23 in Pediatric Phosphate Physiology and X-linked Hypophosphatemic Rickets.

描述（由申请人提供）：长期目标是建立代谢性骨研究的专业知识，表征成纤维细胞生长因子-23 （FGF23）在儿童年龄谱中的调节，并探索该激素在磷酸盐消耗障碍中的病理生理学，以优化这些疾病的治疗。FGF23是磷酸盐和维生素D代谢的关键调节因子，FGF23失调是x连锁低磷血症佝偻病（XLH）的核心。儿童的血清磷酸盐浓度高于成人，这可能是由FGF23介导的。关于FGF23对健康儿童磷酸盐和骨骼代谢的影响，骨化三醇和磷酸盐治疗XLH对FGF23的影响，或FGF23对XLH治疗不良结局的影响，目前知之甚少。这种知识的缺乏不利于XLH治疗的安全性。总的假设是，FGF23对生长中的儿童正常的磷酸盐稳态很重要，而FGF23失调对磷酸盐消耗综合征至关重要。我们假设FGF23浓度随儿童时期的年龄、种族和性别而变化，并与磷酸盐代谢参数和骨矿物质含量有关（Aim 1）。我们将测量0 - 16岁的健康黑人和白人男孩和女孩的血清FGF23，以及血液和尿液的生物化学（在一个子集中进行骨矿物质含量评估）。为了验证XLH中FGF23水平受骨化三醇和磷酸盐治疗影响并预测疾病结局的假设（目的2），我们将在一项前瞻性研究中招募XLH患者，测量一系列FGF23浓度以及XLH治疗的临床重要结果，包括治疗的主要副作用。这些研究将导致XLH治疗方法的改进。该奖项将允许首席研究者在一个强大的指导环境中进行临床研究，同时参与骨特异性研究技术（包括骨组织形态学和定量计算机断层扫描）的教学课程和专业培训，增强他未来作为独立研究者的成功。

DESCRIPTION (provided by applicant): 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.