REGULATIOIN OF RENAL PHOSPHATE EXCRETION AND VITAMIN D METABOLISM BY FGF 7

FGF 7 对肾磷酸盐排泄和维生素 D 代谢的调节

• 批准号: 7314460
• 负责人: RAJIV KUMAR
• 金额: $ 31.43万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7314460
• 关键词: Acute; Address; Animal Model; Applications Grants; Biological; Bone Diseases; Cells; Chronic; Condition; Data; Diet; Dihydroxycholecalciferols; Disease; Dose; Epithelial Cells; Excretory function; Extracellular Matrix; FGF7 gene; Familial hypophosphatemic bone disease; Fibroblast Growth Factor; Genes; Growth Factor; Homeostasis; Hypophosphatemia; Kidney; Knockout Mice; Knowledge; Measures; Mesenchymal; Messenger RNA; Metabolism; Methods; Micropuncture; Mitogen-Activated Protein Kinase Kinases; Mitogens; Mixed Function Oxygenases; Molecular Weight; Mus; Nephrons; Osteoblasts; Osteomalacia; Pathogenesis; Pathway interactions; Patients; Peptides; Phenotype; Phosphotransferases; Physiologic calcification; Physiological; Play; Process; Production; Property; Proteins; Rattus; Regulation; Relative (related person); Reporting; Research Personnel; Rickets; Role; Serum; Signal Pathway; Signal Transduction; Skin; Sodium; Testing; Tissues; Vitamin D; Vitamins; beta catenin; bone; design; fibroblast growth factor 23; human SFRP4 protein; in vivo; inorganic phosphate; keratinocyte growth factor; knockout gene; mineralization; paracrine; programs; protein expression; rat secreted frizzled-related protein 4; receptor; renal epithelium; research study; response; sodium-phosphate cotransporter proteins; tumor; uptake; wasting

DESCRIPTION (provided by applicant): The objective of this grant proposal is to determine the physiological role and mechanism of action of a phosphaturic factor, FGF 7, and to establish its role in the pathogenesis of hypophosphatemic diseases. Our hypothesis is that FGF 7 is a potent PTN that inhibits Wnt signaling, thereby reducing renal Pi reabsorption. We will first determine whether FGF 7 has properties of a PTN. We will assess how the activity of FGF 7 is related to that of other PTNs by determining whether FGF 7 alters Wnt signaling and whether it plays a role in the pathogenesis of hypophosphatemic diseases. In aim 1, we will investigate whether FGF 7 has properties similar to those of other PTNs, FGF-23 and sFRP-4. The activity of FGF 7 will be compared with that of other PTNs such as FGF-23 and sFRP-4. We will determine if FGF 7 alters vitamin D metabolism by measuring serum 1,25(OH)2D concentrations in rats following administration of FGF 7. The effect of FGF 7 on 25(OH)D1(OH)ase activity, mRNA and protein expression will be assessed. The capacity of FGF 7 to inhibit bone mineralization will be examined. The biological effects of FGF 7 administration will be confirmed by examining the phenotype of Fgf 7 gene knockout mice. In aim 2, we will determine the nephron segment in which FGF 7 is active, and we will investigate whether FGF 7 inhibits Pi transport by reducing the activity, amount and distribution of the renal Na+Pi cotransporter. Aim 3 is designed to establish signaling pathways (receptor kinase/MAPK and Wnt/beta-catenin) involved in the inhibition of Pi uptake by FGF 7. In aim 4, we will determine if serum FGF 7 is increased in patients with TIO and XLH and in animal models of XLH. The modulation of FGF 7 by diets high or low in Pi content will be assessed to determine whether alterations in serum Pi induced by dietary changes in Pi, influence FGF 7 similarly to the hypophosphatemia in patients or animal models with renal Pi wasting. In aim 5, we will assess the relative contribution of the PTNs, FGF 7, FGF-23 and sFRP-4, to the pathogenesis of hypophosphatemia seen in animal models of renal Pi wasting. Significance: Our experiments will define a role for FGF 7 in Pi homeostasis, the regulation of vitamin D metabolism, and bone mineralization and will delineate the pathophysiologic role of FGF 7 in diseases such as TIO and XLH. The interaction between the FGF 7 and other PTNs will be clarified. Such information will significantly enhance our knowledge of mineralization processes and Pi homeostasis.

描述（由申请人提供）：本拨款提案的目的是确定磷酸盐因子 FGF 7 的生理作用和作用机制，并确定其在低磷血症疾病发病机制中的作用。我们的假设是 FGF 7 是一种有效的 PTN，可抑制 Wnt 信号传导，从而减少肾 Pi 重吸收。我们首先确定FGF 7是否具有PTN的特性。我们将通过确定 FGF 7 是否改变 Wnt 信号传导以及它是否在低磷血症疾病的发病机制中发挥作用，评估 FGF 7 的活性如何与其他 PTN 的活性相关。在目标 1 中，我们将研究 FGF 7 是否具有与其他 PTN、FGF-23 和 sFRP-4 相似的特性。 FGF 7 的活性将与其他 PTN（例如 FGF-23 和 sFRP-4）的活性进行比较。我们将通过测量给予 FGF 7 后大鼠血清 1,25(OH)2D 浓度来确定 FGF 7 是否改变维生素 D 代谢。FGF 7 对 25(OH)D1(OH)ase 活性、mRNA 和蛋白质表达的影响将被评估。将检查 FGF 7 抑制骨矿化的能力。 FGF 7 给药的生物学效应将通过检查 Fgf 7 基因敲除小鼠的表型来证实。在目标 2 中，我们将确定 FGF 7 处于活跃状态的肾单位段，并研究 FGF 7 是否通过降低肾脏 Na+Pi 协同转运蛋白的活性、数量和分布来抑制 Pi 转运。目标 3 旨在建立参与 FGF 7 抑制 Pi 摄取的信号通路（受体激酶/MAPK 和 Wnt/β-连环蛋白）。在目标 4 中，我们将确定 TIO 和 XLH 患者的血清 FGF 7 是否升高以及 XLH 动物模型。将评估 Pi 含量高或低的饮食对 FGF 7 的调节，以确定 Pi 饮食变化引起的血清 Pi 的变化是否会影响 FGF 7，类似于肾 Pi 消耗的患者或动物模型中的低磷血症。在目标 5 中，我们将评估 PTN、FGF 7、FGF-23 和 sFRP-4 对肾 Pi 消耗动物模型中低磷血症发病机制的相对贡献。 意义：我们的实验将确定 FGF 7 在 Pi 稳态、维生素 D 代谢调节和骨矿化中的作用，并将描述 FGF 7 在 TIO 和 XLH 等疾病中的病理生理作用。 FGF 7 和其他 PTN 之间的相互作用将得到澄清。这些信息将显着增强我们对矿化过程和 Pi 稳态的了解。