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.
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