Biology of a Novel Phosphaturic Protein - sFRP-4

描述（申请人提供）：本授权申请的目的是研究一种新的磷酸尿因子，分泌型卷曲相关蛋白-4（sFRP-4）的作用机制，sFRP-4是导致肿瘤诱导的骨软化症患者中出现的磷酸尿、低磷酸盐血症和不适当适应的25-羟基维生素D3 1 α-羟化酶（25（OH）D3 1 α OHase）活性的因子之一，并确定其是否调节正常生理状态下的磷酸盐（Pi）稳态。本申请的假设如下：（1）sFRP-4通过两种不同的机制调节无机磷酸盐（Pi）体内平衡：（a）抑制肾近端小管Pi重吸收;（B）抑制肾25（OH）D3 1 α（OH）酶活性和1 α，25-二羟基维生素D合成。这些作用减少肠Pi吸收和肾Pi重吸收，并且可能通过sFRP-4对Wnt信号传导途径的作用来调节。(2)肾脏和循环sFRP-4受膳食Pi摄入量调节。本申请的具体目的如下：（1）确定sFRP-4在大鼠或小鼠肾单位中的作用部位和作用机制。(2)确定sFRP-4分子磷酸尿效应的结构基础。(3)研究sFRP-4抑制近端肾小管细胞25（OH）D3 1 α（OH）酶活性的生理机制。(4)检查sFRP-4在近端小管中激活的信号通路。(5)确定血清和肾脏中sFRP-4浓度是否因膳食Pi摄入量的变化而改变。重要性：虽然维生素D内分泌系统和PTH已被描述为钙和Pi稳态的调节剂，但尚未描述主要调节Pi稳态的分子或系统，sFRP-4可能是这样的分子。我们认为sFRP-4是这方面的重要分子，因此了解它在肾脏中的功能和调节方式至关重要。我们的研究结果将有重要的意义方面的Pi稳态，在哺乳动物和人类的骨矿化，并通过Wnt信号在肾脏中的离子转运的调节。

DESCRIPTION (provided by applicant): The objective of this grant application is to examine the mechanism of action of a novel phosphaturic factor, secreted frizzled-related protein-4 (sFRP-4), one of the factors responsible for the phosphaturia, hypophosphatemia and inappropriately adapted 25-hydroxyvitamin D3 1 alpha-hydroxylase (25(OH) D3 1alphaOHase) activity seen in patients with tumor-induced osteomalacia, and to determine whether it regulates phosphate (Pi) homeostasis in normal physiological states. The hypotheses of this application are as follows: (1) sFRP-4 regulates inorganic phosphate (Pi) homeostasis by two distinct mechanisms: (a) inhibiting renal proximal tubule Pi reabsorption; (b) inhibiting renal 25(OH) D3 1alpha (OH)ase activity and 1alpha, 25-dihydroxyvitamin D synthesis. These actions reduce intestinal Pi absorption and renal Pi reabsorption and are likely modulated by the effects of sFRP-4 on the Wnt signaling pathway. (2) Renal and circulating sFRP-4 is regulated by dietary Pi intake. The specific aims of the application are as follows: (1) To determine the site and mechanism of action of sFRP-4 in rat or mouse nephron. (2) To determine the structural basis for the phosphaturic effects of the sFRP-4 molecule. (3) To examine the physiological mechanisms by which sFRP-4 inhibits 25(OH)D3 1alpha (OH)ase activity in the proximal tubular cell. (4) To examine the signaling pathways activated in the proximal tubule by sFRP-4. (5) To determine whether sFRP-4 concentrations in the serum and kidney are altered by changes in the intake of dietary Pi. Significance: While the vitamin D endocrine system and PTH have been described as modulators of calcium and Pi homeostasis, no molecules or systems have been described that predominantly regulate Pi homeostasis, sFRP-4 may be such a molecule. We believe that sFRP-4 is an important molecule in this regard, and it is therefore critical to understand how it functions and is regulated in the kidney. Our findings will have important implications with respect to Pi homeostasis, bone mineralization in mammals and humans, and the regulation of ion transport through Wnt signaling in the kidney.