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）：该赠款提案的目的是确定磷酸因子，FGF 7的生理作用和作用机理，并确定其在低磷症疾病发病机理中的作用。我们的假设是，FGF 7是一种有效的PTN，可抑制Wnt信号传导，从而减少肾脏PI的重吸收。我们将首先确定FGF 7是否具有PTN的属性。我们将通过确定FGF 7是否改变了Wnt信号传导以及它是否在低磷酸血症疾病的发病机理中起作用，我们将评估FGF 7的活性与其他PTN的活性如何相关。在AIM 1中，我们将研究FGF 7是否具有类似于其他PTN的属性，即FGF-23和SFRP-4。 FGF 7的活性将与其他PTN（例如FGF-23和SFRP-4）进行比较。我们将通过测量FGF 7后大鼠的1,25（OH）2D浓度来确定FGF 7是否改变了维生素D代谢。将评估FGF 7对25（OH）D1（OH）ASE ASE活性，mRNA和蛋白质表达的影响。将检查FGF 7抑制骨矿化的能力。 FGF 7给药的生物学作用将通过检查FGF 7基因敲除小鼠的表型来确认。在AIM 2中，我们将确定FGF 7处于活动状态的肾单位段，我们将通过减少肾脏Na+Pi cotransporter的活性，数量和分布来抑制PI运输。 AIM 3旨在建立参与FGF 7抑制PI摄取PI摄取的信号通路（受体激酶/MAPK和Wnt/Beta-catenin）。在AIM 4中，我们将确定TIO和XLH的患者以及XLH动物模型中的TIO和XLH患者的血清FGF 7是否增加。将评估最高或低PI含量的饮食对FGF 7的调节，以确定PI饮食变化引起的血清PI的改变，与患者或肾脏PI浪费的动物模型中的低磷酸血症相似，会影响FGF 7。在AIM 5中，我们将评估PTN，FGF 7，FGF-23和SFRP-4的相对贡献对肾脏PI浪费动物模型中低磷酸血症的发病机理。 意义：我们的实验将定义FGF 7在PI稳态中的作用，维生素D代谢的调节和骨矿化的作用，并描述FGF 7在TIO和XLH等疾病中的病理生理作用。 FGF 7与其他PTN之间的相互作用将被澄清。这些信息将大大增强我们对矿化过程和PI稳态的了解。