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

成纤维细胞生长因子 23：昼夜节律

• 批准号: 7377657
• 负责人: HOWARD J HELLER
• 金额: $ 0.41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377657
• 关键词: FIBROBLAST; GROWTH; FACTOR; 23; CIRCADIAN

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。血磷是人体内的一个重要因素，血磷紊乱会导致有害后果。重度低磷血症的后果包括溶血、组织缺氧、脑病、横纹肌溶解、肌无力、心肌病、代谢性酸中毒、高钙尿、高镁尿和骨矿化受损。低磷血症的后果包括低钙血症、手足抽搐和软组织钙化。对磷酸盐生理学的进一步了解可能会在磷酸盐紊乱、骨紊乱、肾结石、终末期肾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，磷酸盐生理学仍然知之甚少。成纤维细胞生长因子23（FGF 23）最近已被证明通过减少肾磷酸盐重吸收降低血磷，并降低血清1，25-二羟维生素D（1，25-D）。血磷显示活跃的昼夜变化，这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子。FGF 23可能会发挥这一作用。虽然一项小型的人体研究没有证明FGF 23的昼夜节律，但它是不敏感的检测方法。在目标1中，我们将使用更灵敏的测定来评估血液FGF 23的昼夜变化，并且我们将确定变化模式是否与FGF 23在驱动血磷酸盐的昼夜节律中的直接作用一致。 越来越多的证据表明，FGF 23可能是血磷的激素调节剂。在动物研究中，循环FGF 23在高磷酸盐饮食（150至250 pg/ml）下增加，并且这种作用通过添加高饮食钙（>1600 pg/ml）而显著增强。尽管一些人类研究表明，增加膳食磷酸盐或口服磷酸盐负荷可能会提高FGF 23，但尚未测试FGF 23对人类口服钙负荷的反应。在目标2中，我们将评估磷酸盐或钙的急性负荷是否影响血液FGF 23。高尿钙肾结石患者口服钙负荷后血清和尿钙的增量大于正常志愿者。因此，他们的FGF 23反应应该被放大。在目标3中，我们将比较高钙尿症和非高钙尿症结石形成者之间FGF 23对口服钙负荷的反应。这项小型探索性研究旨在生成证明R21补助金合理性的初步数据。