Dietary and hormonal regulation of FGF-23 in humans

人类 FGF-23 的饮食和激素调节

• 批准号: 7880829
• 负责人: SHERRI-ANN M BURNETT-BOWIE
• 金额: $ 14.8万
• 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 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880829
• 关键词: Affect; Animals; Blood; Bone Diseases; Calcium; Chronic Kidney Failure; Circadian Rhythms; Clinical; Complement; Data; Development; Diet Research; Dihydroxycholecalciferols; Disease; Dose; Endocrine; Estradiol; Excretory function; Familial hypophosphatemic bone disease; Fatty acid glycerol esters; Feedback; Freezing; Glomerular Filtration Rate; Goals; Homeostasis; Hormonal; Hormones; Hour; Human; Hypophosphatemia; Infusion procedures; Inherited; Kidney; Kidney Failure; Knowledge; Link; Measures; Medical; Metabolism; Muscle function; Normal Range; Osteomalacia; Parathyroid Hormones; Patients; Physiologic calcification; Physiological; Physiology; Placebos; Play; Potassium Phosphate/Sodium Phosphate; Production; Proteins; Protocols documentation; Proximal Kidney Tubules; Randomized; Rare Diseases; Regulation; Renal clearance function; Research; Role; Sampling; Serum; Signal Transduction; Sodium; Standardization; Stimulus; Supplementation; System; Testing; Testosterone; Therapeutic; Time; Urine; Vitamin D; Withdrawal; arm; base; cinacalcet; fibroblast growth factor 23; healthy volunteer; hormone regulation; human PTH protein; inorganic phosphate; male; men; novel; parathyroid hyperplasia; prevent; sodium-phosphate cotransporter proteins; tumor; urinary; volunteer; wasting

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 (PO4) 对于骨矿化、肌肉功能、信号转导以及能量的产生和利用至关重要。 PO4 处理异常以低磷血症性佝偻病和慢性肾衰竭伴甲状旁腺增生和骨营养不良的形式出现。三种 PO4 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发的骨软化症）的数据表明，成纤维细胞生长因子 23 (FGF-23) 是一种新型磷酸盐激素，导致这些罕见患者严重磷酸盐消耗。该提案的总体目标是描述 FGF-23 在正常 P04 生理学中的作用以及调节 FGF-23 的因素。在每个方案中，我们将测量 FGF-23、血液和尿液 PO4，以及已知影响 PO4 的其他激素，如甲状旁腺激素 (PTH) 和 1,25 二羟基维生素 D。在具体目标 1 中，20 名健康受试者将采用研究饮食，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。我们假设通过余弦分析测量的 FGF-23 的昼夜变化与血液 PO4 和 PO4 肾清除率的变化平行，但与 PTH 的变化不同。在具体目标 2 中，100 名缺乏维生素 D 的健康受试者将被随机分配接受钙 500 mg BID 或钙 500 mg BID 加维生素 D 50,000 单位 Q WK，为期 12 周，以确定在控制血液 PO4 和 PTH 变化后，维生素 D 是否会增加 FGF-23 水平。为了确定 PTH 抑制对 FGF-23 的影响，在具体目标 3 中，44 名健康受试者将被随机分配服用安慰剂或拟钙剂西那卡塞 30 mg QD（降低 PTH 水平），同时服用磷酸盐，以确定 P04 负荷是否会独立于 PTH 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 58 名健康男性的 FGF-23，这些男性以 0.55 U/kg/hr 的剂量输注人 PTH(1-34)，以确定 PTH 是否对人体内的 FGF-23 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发挥着至关重要的作用。该提案中的研究将增进我们对人类 FGF-23 激素调节的理解，并可能有助于开发针对低磷或高磷血症患者的新疗法。