MOLECULAR PATHOGENESIS OF HYPOPHOSPHATEMIC RICKETS

描述（由申请人提供）：通过对获得性和遗传性低磷血症的研究，对磷酸盐稳态的激素调节机制有了新的认识。FGF-23在多种形式的低磷血症佝偻病的病理生理中起核心作用，包括肿瘤诱导的骨软化症（TIO）、x连锁低磷血症佝偻病（XLH）和常染色体显性低磷血症佝偻病（ADHR）。然而，这种有效的近端肾小管磷酸盐运输抑制剂调节主要激素反应性钠依赖性磷酸盐转运蛋白（NaPi-lla）的机制实际上尚未被探索。我们假设FGF-23通过激活FGF受体促进NaPi-lla的内化，从而抑制钠依赖性磷酸盐运输。此外，内化是通过在与肌动蛋白细胞骨架相互作用的钠氢离子交换相关因子-1 （NHERF-1）支架上组装包含napi - la和信号分子的大分子复合物来完成的。在Specific Aim 1中，我们将确定FGF-23是否通过已知的fgfr促进NaPi-lla内化。我们将进一步确定导致麻醉品贩运的主要信号通路。在Specific Aim 2中，我们将研究NHERF-1在FGF-23介导的NaPi-lla内化中的作用。在Specific Aim 3中，我们将确定NHERF-1结合伙伴，用于整合FGF-23信号和NaPi-lla内化。本提案中概述的实验将建立FGF-23调节近端肾小管中磷酸盐处理的机制，包括控制NaPi-lla运输，激活细胞信号通路以及整合信号和NaPi-lla膜定位的NHERF-1依赖性多蛋白复合物的组装。更好地了解FGF-23信号及其对肾脏磷酸盐处理和最终骨骼矿化的影响将为磷酸盐稳态紊乱提供新的治疗靶点。

DESCRIPTION (provided by applicant): Through the study of acquired and inherited hypophosphatemic disorders a new understanding of the hormonal regulators of phosphate homeostasis is emerging. FGF-23 plays a central role in the pathophysiology of several forms of hypophosphatemic rickets including tumor-induced osteomalacia (TIO), X-linked hypophosphatemic rickets (XLH) and autsomal dominant hypophosphatemic rickets (ADHR). However, the mechanism of by which this potent inhibitor of proximal renal tubular phosphate transport modulates the main hormone-responsive sodium-dependent phosphate transporter (NaPi-lla) is virtually unexplored. We hypothesize that FGF-23 inhibits sodium-dependent phosphate transport by promoting internalization of NaPi-lla via activation of FGF receptors. Furthermore, internalization is accomplished by the assembly of a macromolecular complex involving NaPi-lla and signaling molecules on the scaffold of Sodium hydrogen ion exchanger related factor-1 (NHERF-1) that interacts with the actin cytoskeleton. In Specific Aim 1, we will determine if FGF-23 acts via known FGFRs to promote NaPi-lla internalization. We will further define the major signaling pathway(s) responsible for NaPi-lla trafficking. In Specific Aim 2, we will examine role of NHERF-1 in FGF-23 mediated internalization of NaPi-lla. In Specific Aim 3, we will identify NHERF-1 binding partners which serve to integrate FGF-23 signaling and NaPi-lla internalization. The experiments outlined in this proposal will establish the mechanism by which FGF-23 regulates phosphate handling in the proximal renal tubule including control of NaPi-lla trafficking, activation of the cell signaling pathways and the assembly of NHERF-1 dependent multiprotein complexes that integrate signaling and NaPi-lla membrane localization. A better understanding of FGF-23 signaling and its consequences for renal phosphate handling and ultimately skeletal mineralization will provide new therapeutic targets for disorders of phosphate homeostasis.