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

描述（由申请人提供）：本基金提案的目的是确定磷酸尿因子FGF 7的生理作用和作用机制，并确定其在低磷酸盐血症疾病发病机制中的作用。我们的假设是FGF 7是抑制Wnt信号传导的有效PTN，从而减少肾Pi重吸收。我们将首先确定FGF 7是否具有PTN的性质。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起作用来评估FGF 7的活性与其他PTNs的活性之间的关系。在目的1中，我们将研究FGF 7是否具有与其他PTNs、FGF-23和sFRP-4相似的性质。将FGF 7的活性与其它PTNs如FGF-23和sFRP-4的活性进行比较。我们将通过测定给予FGF 7后大鼠血清中1，25（OH）2D浓度来确定FGF 7是否改变维生素D代谢。将评估FGF 7对25（OH）D1（OH）酶活性、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具有活性的肾单位段，并研究FGF 7是否通过降低肾Na+Pi协同转运蛋白的活性、数量和分布来抑制Pi转运。目的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患者以及XLH动物模型中血清FGF 7是否升高。将评估通过高或低Pi含量的饮食对FGF 7的调节，以确定由Pi的饮食变化诱导的血清Pi的改变是否与肾Pi消耗患者或动物模型中的低磷酸盐血症类似地影响FGF 7。在目的5中，我们将评估PTNs、FGF 7、FGF-23和sFRP-4对肾Pi消耗动物模型中观察到的低磷酸盐血症发病机制的相对贡献。 重要性：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在诸如TIO和XLH的疾病中的病理生理作用。FGF 7和其他PTNs之间的相互作用将被阐明。这些信息将显着提高我们的矿化过程和Pi稳态的知识。

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.