Dietary and hormonal regulation of FGF-23 in humans

人类 FGF-23 的饮食和激素调节

• 批准号: 7147855
• 负责人: SHERRI-ANN M BURNETT-BOWIE
• 金额: $ 14.55万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147855
• 关键词: 1,25 dihydroxycholecalciferol; blood chemistry; circadian rhythms; clinical research; dietary calcium; dietary control; fibroblast growth factor; hormone regulation /control mechanism; human subject; nutrition related tag; parathyroid hormones; patient oriented research; phosphates; phosphorus metabolism; vitamin D deficiency

DESCRIPTION (provided by applicant): Phosphate (PO4) is essential for bone mineralization, muscle function, signal transduction and the creation and utilization of energy. Abnormal PO4 handling occurs in forms of hypophosphatemic rickets, and in chronic renal failure with resultant parathyroid hyperplasia and osteodystrophy. Data from three PO4 wasting disorders (X-linked hypophosphatemia, autosomal dominant hypophosphatemic rickets, and tumor induced osteomalacia) demonstrate that fibroblast growth factor 23 (FGF-23) is a novel phosphaturic hormone that is responsible for severe phosphate wasting in these rare patients. The overarching goal of this proposal is to describe the role of FGF-23 in normal P04 physiology and factors that regulate FGF-23. In each of these protocols, we will measure FGF-23, blood and urinary PO4, and other hormones known to affect PO4, like parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D. In Specific Aim 1, 20 healthy subjects will consume a research diet, and undergo 24 hour blood and urine frequent sampling to assess the diurnal variation in FGF-23. We hypothesize that the diurnal variation in FGF-23, as measured by cosinor analysis, will parallel that of blood PO4 and the renal clearance of PO4, and differ from that of PTH. In Specific Aim 2, 100 healthy vitamin D-deficient subjects will be randomly assigned to calcium 500 mg BID or calcium 500 mg BID plus vitamin D 50,000 units Q WK for 12 weeks to determine whether vitamin D increases FGF-23 levels after controlling for changes in blood PO4 and PTH. To determine the effects of PTH suppression on FGF-23, in Specific Aim 3, 44 healthy subjects will be randomly assigned to either placebo or a calcimimetic, Cinacalcet 30 mg QD (which lowers PTH levels), and concurrently phosphate loaded to determine whether P04 loading increases FGF-23 levels independently of PTH. Finally, to determine effect of PTH stimulation on FGF-23, in Specific Aim 4, we will measure FGF-23 in 58 healthy men who were infused with human PTH(1-34) at a dose of 0.55 U/kg/hr to determine whether PTH has a direct effect on FGF-23 in humans. To summarize, FGF-23 is responsible for phosphate wasting in several rare disorders and appears to play a vital role in normal phosphate physiology. The studies in this proposal will advance our understanding of the hormonal regulation of FGF-23 in humans and may help in the development of novel treatments for patients with hypo- or hyperphosphatemic disorders.

描述（由申请人提供）： 磷酸盐（PO 4）对于骨矿化、肌肉功能、信号传导以及能量的产生和利用至关重要。异常的PO 4处理以低磷酸盐血症性佝偻病的形式发生，并且在慢性肾衰竭中导致甲状旁腺增生和骨营养不良。来自三种PO 4消耗性疾病（X连锁低磷血症、常染色体显性低磷血症性佝偻病和肿瘤诱导的骨软化症）的数据表明，成纤维细胞生长因子23（FGF-23）是一种新型磷酸尿激素，可导致这些罕见患者的严重磷酸盐消耗。该提案的首要目标是描述FGF-23在正常P04生理学中的作用和调节FGF-23的因子。在这些方案中，我们将测量FGF-23，血液和尿液PO 4以及其他已知影响PO 4的激素，如甲状旁腺激素（PTH）和1，25二羟维生素D。在特定目标1中，20名健康受试者将食用研究饮食，并进行24小时血液和尿液频繁采样以评估FGF-23的昼夜变化。我们假设FGF-23的昼夜变化，如余弦分析所测量的，将平行于血PO 4和肾清除PO 4，并不同于PTH。在特定目标2中，100名健康维生素D缺乏受试者将被随机分配至钙500 mg BID或钙500 mg BID加维生素D 50，000单位QWK组，持续12周，以确定在控制血液PO 4和PTH的变化后，维生素D是否增加FGF-23水平。为了确定PTH抑制对FGF-23的影响，在特定目标3中，将44名健康受试者随机分配至安慰剂或拟钙剂西那卡塞30 mg QD（其降低PTH水平），并同时负载磷酸盐以确定P 04负载是否独立于PTH而增加FGF-23水平。最后，为了确定PTH刺激对FGF-23的影响，在具体目标4中，我们将测量以0.55 U/kg/hr的剂量输注人PTH（1-34）的58名健康男性中的FGF-23，以确定PTH是否对人体中的FGF-23具有直接影响。总而言之，FGF-23是导致几种罕见疾病中磷酸盐消耗的原因，并且似乎在正常磷酸盐生理学中起着至关重要的作用。本提案中的研究将促进我们对人类FGF-23激素调节的理解，并可能有助于开发低磷或高磷血症患者的新治疗方法。