FIBROBLAST GROWTH FACTOR 23: CIRCADIAN RHYTHM & RESPONSE TO ORAL LOAD OF CA OR P

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。血磷是人体内的一个重要因素，血磷紊乱会导致不良后果。严重低磷血症的后果包括溶血、组织缺氧、脑病、横纹肌溶解、肌肉无力、心肌病、代谢性酸中毒、高钙尿、高镁尿和骨矿化障碍。低磷血症的后果包括低钙血症、手足抽搐和软组织钙化。提高对磷酸盐生理学的理解可能会在磷酸盐疾病、骨病、肾结石、终末期肾脏疾病和心血管疾病的管理中产生重要的新应用。尽管取得了许多进展，但人们对磷酸盐生理学仍知之甚少。成纤维细胞生长因子23(FGF23)最近被证明通过减少肾脏磷酸盐重吸收和降低血清1，25-二羟基维生素D(1，25-D)来降低血磷。血磷表现出活跃的昼夜节律变化，这种变化不是由甲状旁腺激素(PTH)驱动的，尽管许多人认为PTH是血磷的主要调节因素。相反，FGF23可能会发挥这一作用。尽管一项针对人类的小型研究没有证明FGF23的昼夜节律，但它在一项不敏感的测试中存在缺陷。在目标1中，我们将使用更灵敏的方法评估血液中FGF23的昼夜变化，并确定这种变化模式是否与FGF23在驱动血磷昼夜节律中的直接作用一致。越来越多的证据表明，FGF23可能是血磷的激素调节因子。在动物研究中，循环中的FGF23在高磷饮食(150至250 pg/ml)时增加，这种影响在添加高钙饮食(&gt；1600 pg/ml)时显著增强。尽管一些人体研究表明，增加膳食磷酸盐或口服磷酸盐负荷可能会增加FGF23，但FGF23对人体口服钙负荷的反应尚未得到测试。在目标2中，我们将评估急性磷酸盐或钙负荷是否影响血液FGF23。与正常志愿者相比，高钙尿性肾结石患者口服钙负荷后血钙和尿钙的增加幅度更大。因此，它们的FGF23反应应该被放大。在目标3中，我们将比较高钙尿性和非高钙尿性结石患者FGF23对口服钙负荷的反应。这项小型探索性研究旨在产生初步数据，证明R21拨款是合理的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Blood phosphate is an important factor in the body, and disorders of blood phosphate result in deleterious consequences. Consequences of severe hypophosphatemia include hemolysis, tissue hypoxia, encephalopathy, rhabdomyolysis, muscle weakness, cardiomyopathy, metabolic acidosis, hypercalciuria, hypermagnesuria and impairment of bone mineralization. Consequences of hypophosphotemia include hypocalcemia, tetany, and calcification of the soft tissues. Improved understanding of phosphate physiology may yield important new applications in the management of phosphate disorders, bone disorders, kidney stones, end-stage renal disease and cardiovascular disease. Despite many advances, phosphate physiology is still poorly understood. Fibroblast growth factor 23 (FGF23) has recently been shown to decrease blood phosphate by reducing renal phosphate reabsorption and to decrease serum 1,25-dihydroxyvitamin D (1,25-D). Blood phosphate demonstrates active circadian variation that is not driven by parathyroid hormone (PTH), even though PTH is believed by many to be the primary regulator of blood phosphate. FGF23 may instead fulfill that role. Although one small study in humans did not demonstrate circadian rhythm of FGF23, it was flawed by an insensitive assay. In Aim 1, we will assess circadian variation in blood FGF23 using a more sensitive assay, and we will determine whether the pattern of change is consistent with a direct role of FGF23 in driving the circadian rhythm of blood phosphate. Accumulating evidence suggests that FGF23 may be a hormonal regulator of blood phosphate. In animal studies, circulating FGF23 increases on high phosphate diets (150 to 250 pg/ml), and this effect is markedly augmented by addition of high dietary calcium (>1600 pg/ml). Although a few studies in humans have shown that increasing dietary phosphate or oral phosphate load may raise FGF23, the response of FGF23 to an oral calcium load in humans has not been tested. In Aim 2, we will assess whether acute loads of phosphate or calcium affect blood FGF23. Hypercalciuric kidney stone-formers demonstrate greater increment in serum and urine calcium with oral calcium load than normal volunteers. Thus, their FGF23 response should be amplified. In Aim 3, we will compare FGF23 response to oral calcium load between hypercalciuric and nonhypercalciuric stone-formers. This small exploratory study is designed to generate preliminary data justifying an R21 grant.