Biology of a Novel Phosphaturic Protein - sFRP-4

描述(申请人提供)：这项拨款申请的目的是研究一种新的磷酸因子--分泌型卷曲相关蛋白-4(SFRP-4)的作用机制，它是导致肿瘤引起的骨软化症患者出现磷酸尿、低磷血症和不适当适应的25-羟基维生素D31α-羟基酶(25(OH)D31αOHase)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)动态平衡。这一应用的假设如下：(1)SFRP-4通过两种不同的机制调节无机磷(PI)的动态平衡：(A)抑制肾近端小管对PI的重吸收；(B)抑制肾脏25(OH)D31α(OH)酶的活性和1α，25-二羟基维生素D的合成。这些作用减少了肠道对PI的吸收和肾脏对PI的重吸收，并可能受到SFRP-4对Wnt信号通路的影响。(2)肾脏和循环中的SFRP-4受膳食PI摄入量的调节。应用的具体目的如下：(1)确定SFRP-4在大鼠或小鼠肾单位的作用部位和作用机制。(2)确定SFRP-4分子的磷酸化效应的结构基础。(3)探讨SFRP-4抑制近端肾小管上皮细胞25(OH)D31α(OH)酶活性的生理机制。(4)检测SFRP-4激活近曲小管的信号通路。(5)测定血清和肾脏中SFRP-4的浓度是否因膳食PI摄入量的改变而改变。意义：虽然维生素D内分泌系统和甲状旁腺素被描述为钙和PI稳态的调节者，但还没有被描述为主要调节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。我们的发现将对哺乳动物和人类体内的PI动态平衡、骨矿化以及通过Wnt信号调节肾脏中的离子转运具有重要意义。

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.