Biology of a Novel Phosphaturic Protein - sFRP-4

描述（由申请人提供）：本资助申请的目的是研究一种新的磷酸化因子的作用机制，分泌的毛状相关蛋白-4 （sFRP-4）是导致肿瘤诱导的骨软化症患者中出现的磷尿症、低磷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 -羟化酶）活性的因素之一，并确定它是否调节正常生理状态下的磷酸盐（Pi）稳态。该应用的假设如下：(1)sFRP-4通过两种不同的机制调节无机磷酸盐（Pi）的稳态：(a)抑制肾近端小管Pi的重吸收；(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。这些作用减少肠道Pi吸收和肾脏Pi重吸收，可能是由sFRP-4对Wnt信号通路的影响所调节的。(2)肾脏和循环中strp -4受日粮Pi摄入量的调节。应用的具体目的如下：(1)确定sFRP-4在大鼠或小鼠肾细胞中的作用部位和作用机制。(2)确定sFRP-4分子磷酸化作用的结构基础。(3)探讨sFRP-4抑制近端小管细胞25(OH)D3 1 α (OH)酶活性的生理机制。(4)探讨sFRP-4在近端小管中激活的信号通路。(5)测定血清和肾脏中sFRP-4浓度是否随日粮Pi摄入量的变化而改变。意义：虽然维生素D内分泌系统和甲状旁腺激素被描述为钙和Pi稳态的调节剂，但没有描述主要调节Pi稳态的分子或系统，但sFRP-4可能就是这样的分子。我们认为sFRP-4在这方面是一个重要的分子，因此了解它在肾脏中的功能和调节是至关重要的。我们的研究结果将对Pi稳态、哺乳动物和人类的骨矿化以及通过Wnt信号在肾脏中调节离子运输具有重要意义。

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.