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

描述（由申请方提供）：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（FGF 23）在儿童年龄范围内的调节，并探索该激素在磷酸盐消耗性疾病中的病理生理学，以优化这些疾病的治疗。FGF 23是磷酸盐和维生素D代谢的关键调节剂，并且FGF 23失调是X连锁低磷酸盐血症性佝偻病（XLH）的中心。儿童的血清磷浓度高于成人，这可能是FGF 23介导的。关于FGF 23对健康儿童磷酸盐和骨骼代谢的影响，用骨化三醇和磷酸盐治疗XLH对FGF 23的影响，或FGF 23对XLH治疗不良结局的影响，知之甚少。这种知识的缺乏不利于XLH治疗的安全性。总体假设是，FGF 23在生长期儿童的正常磷酸盐稳态中是重要的，并且FGF 23失调对磷酸盐消耗综合征是至关重要的。我们假设，FGF 23浓度随年龄、种族和性别而变化，并且与磷酸盐代谢和骨矿物质含量参数相关（目的1）。我们将测量血清FGF 23，血液和尿液的生物化学储存样本从健康的黑人和白色男孩和女孩之间的年龄在0和16岁（骨矿物质含量评估的子集）。为了检验XLH中FGF 23水平受骨化三醇和磷酸盐治疗影响的假设并预测疾病结局（目的2），我们将在前瞻性研究中招募XLH受试者，测量系列FGF 23浓度沿着XLH治疗的临床重要结局，包括治疗的主要副作用。这些研究将导致XLH治疗的改善。该奖项将允许主要研究者在强大的指导环境中进行临床研究，同时从事骨特异性研究技术（包括骨组织形态计量学和定量计算机断层扫描）的教学课程和专业培训，提高他作为独立研究者的未来成功。

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.