Dietary and hormonal regulation of FGF-23 in humans

人类 FGF-23 的饮食和激素调节

• 批准号: 7647447
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647447
• 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; Upper arm; Urine; Vitamin D; Withdrawal; 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创造和利用至关重要。异常的PO4处理以低磷酸盐rick鼠的形式发生，以及慢性肾衰竭，导致的甲状旁腺增生和骨dy骨。来自三种PO4浪费障碍的数据（X连锁性低磷酸血症，常染色体显性次磷酸性ri鼠和肿瘤诱导的骨质乳酸）表明，成纤维细胞生长因子23（FGF-23）是一种新型的磷酸激素，导致了这些稀有患者的严重磷酸盐。该提案的总体目标是描述FGF-23在正常P04生理学和调节FGF-23的因素中的作用。 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.我们假设通过COSINOR分析衡量的FGF-23中的昼夜变化将平行于血液PO4和PO4的肾脏清除率，并且与PTH的肾脏清除率不同。在特定的目标2中，100个健康的维生素D缺陷受试者将被随机分配到钙500 mg BID或钙500 mg BID和维生素D 50,000单位Q WK 12周，以确定维生素D在控制血液PO4和PTH后是否会增加FGF-23水平。为了确定PTH抑制对FGF-23的影响，在特定的目标3中，将将健康受试者随机分配到安慰剂或钙化的cinacalcet 30 mg QD（降低PTH水平），并同时负载磷酸盐，以确定P04载荷是否独立于PTH，而P04负载是否会增加FGF-23水平。最后，为了确定PTH刺激对FGF-23的影响，在特定的目标4中，我们将在58名健康的男性中测量FGF-23，这些男性以0.55 U/kg/hr的剂量注入人PTH（1-34），以确定PTH在人类中是否对FGF-23有直接影响。总而言之，FGF-23负责几种罕见疾病的磷酸盐浪费，并且似乎在正常磷酸盐生理学中起着至关重要的作用。该提案中的研究将促进我们对人类FGF-23的激素调节的理解，并可能有助于为低磷酸症患者的患者开发新的治疗方法。