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骨研究的专业知识，确定成纤维细胞生长因子-23(FGF23)在儿童年龄范围内的调节特征，并探索这种激素在磷酸盐消耗障碍中的病理生理学，以优化对这些疾病的治疗。FGF23是磷酸盐和维生素D代谢的关键调节因子，而FGF23失调是X连锁低磷血症性软骨病(XLH)的核心。儿童的血磷浓度高于成人，这可能是FGF23介导的。关于FGF23对健康儿童磷酸盐和骨代谢的影响，骨化三醇和磷酸盐治疗对FGF23的影响，以及FGF23对XLH治疗不良结局的影响，人们知之甚少。这种知识的缺乏不利于XLH治疗的安全性。总体假设是，FGF23对生长中儿童正常的磷酸盐稳态很重要，而FGF23调节失调是磷酸盐消耗综合征的关键。我们假设FGF23浓度在儿童时期随年龄、种族和性别的不同而不同，并与磷酸盐代谢参数和骨矿含量有关(目标1)。我们将测量0至16岁健康黑人和白人男孩和女孩的血清FGF23，以及储存的血液和尿液生化指标(骨矿含量评估在子集中)。为了验证XLHFGF23水平受骨化三醇和磷酸盐治疗的影响并预测疾病结果的假设(目标2)，我们将XLH受试者纳入一项前瞻性研究，测量一系列XLHFGF23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治疗的改进。该奖项将允许首席研究人员在强大的指导环境中从事临床研究，同时从事指导性课程工作和骨骼特定研究技术(包括骨组织形态计量学和定量计算机断层扫描)的专门培训，从而增强他作为独立研究人员未来的成功。

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.