P3: The Structure, Function, and Pharmacologic inhibition of FGF23

成纤维细胞生长因子通过结合和激活一系列受体酪氨酸激酶来调节其生物学反应 (RTK)由四个基因产物组成，命名为FGFR1-FGFR4。FGFR 1-3产生两种异构体 通过不同的配体结合特性和组织表达模式的交替剪接。 FGF23是已知的22个FGFs中最大的一个，它与其他FGFs的不同之处在于其独特的延伸的C-末端 域。X连锁低磷血症(XLH)患者循环中FGF23水平升高，以及 FGF23基因中蛋白酶识别位点的杂合突变会导致一种综合征 XLH型常染色体显性遗传性低磷血症(ADHR)。在ADHR中，对 FGF23分子的蛋白水解性切割可能导致延迟清除和在 发行量。此外，肿瘤引起的骨软化症(TIO)是另一种表型类似于 在许多情况下，作为一种副肿瘤，FGF23被发现是由肿瘤过度产生引起的 综合症。最后，导致循环中完整FGF23水平低的隐性突变会导致肿瘤 钙质沉着症(TC)，一种血清P水平升高的罕见疾病。因此，这些临床观察 已经将FGFs，特别是FGF23在磷酸盐稳态中的新角色归因于FGFs。然而，几乎没有什么是 了解FGF23的作用模式，以及从探索中转化新信息的潜力 这些通向人类疾病的途径是伟大的。 因此，本项目的总体目标是(1)通过成纤维细胞生长因子确定FGF23的细胞信号功能 (2)测定FGF23的原子结构；(3)探讨FGF23的受体特异性 利用特定FGFR亚型缺陷的小鼠模型，(4)建立新的小鼠模型，探索 FGF23在正常和疾病条件下的生物学功能；(5)开发新的药理作用 利用FGFR酪氨酸激酶域小分子抑制剂治疗疾病的研究进展 FGF23功能异常所致。我们的目标将通过应用遗传、生化、 结构和细胞生物学方法，在建立人类疾病模型的基础上发扬光大 后续翻译应用程序。

FGFs mediate their biological responses by binding to and activating a family of receptor tyrosine kinases (RTKs) consisting of four gene products designated FGFR1-FGFR4. FGFR 1-3 have two isoforms produced by alternate splicing which differ in their ligand-binding specificities and tissue expression patterns. FGF23 is the largest of the 22 known FGFs and differs from others by its unique extended C-terminal domain. X-linked hypophosphatemic rickets (XLH) patients have elevated circulating levels of FGF23, and heterozygous mutations within a protease recognition site in the FGF23 gene cause a syndrome that phenocopies XLH, autosomal dominant hypophosphatemic rickets (ADHR). In ADHR, resistance to proteolytic cleavage of the FGF23 molecule presumably leads to delayed clearance and accumulation in the circulation. Furthermore, tumor induced osteomalacia (TIO), another disorder with a similar phenotype to XLH, has been found to be caused in many cases by tumor overproduction of FGF23 as a paraneoplastic syndrome. Finally, recessive mutations resulting in low intact circulating FGF23 levels cause tumoral calcinosis (TC), an unusual disorder in which serum P levels are elevated. Thus these clinical observations have ascribed a novel role for FGFs, and FGF23 in particular, in phosphate homeostasis. However, little is known about the mode of action of FGF23, and the potential for translating new information from exploring these pathways to human diseases is great. Thus, the overall goals of this project are (1) To determine the cell signaling function of FGF23 via FGF receptors, (2) To determine the atomic structure of FGF23, (3) To explore the receptor specificity of FGF23 using murine models deficient in specific FGFR isoforms, (4) To generate new mouse models to explore the biological function of FGF23 in normal and disease conditions, and (5) To develop new pharmacological approaches using small molecule inhibitors of FGFR tyrosine kinase domain for the treatment of diseases caused by abnormal FGF23 function. Our goals will be accomplished by applying genetic, biochemical, structural and cell biological approaches, in the setting of a model human disease in which to carry forward subsequent translational application.