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. ? ? ?
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