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

P3：FGF23 的结构、功能和药理学抑制

• 批准号: 7684865
• 负责人: JOSEPH SCHLESSINGER
• 金额: $ 37.64万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684865
• 关键词: Adult; Alternative Splicing; Animal Model; Applied Genetics; Binding; Biochemical; Biological; Biological Process; Blood Circulation; C-terminal; Calcinosis; Cells; Clinical; Complex; Condition; Disease; Docking; Drug or chemical Tissue Distribution; Embryonic Development; Endocrine; Endopeptidases; Familial hypophosphatemic bone disease; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptor 2; Fibroblast Growth Factor Receptors; Genes; Genetic; Genetically Engineered Mouse; Goals; Heparan Sulfate Proteoglycan; Heparin; Homeostasis; In Vitro; Intervention; Knock-in Mouse; Knockout Mice; Life; Ligand Binding; Mediating; Methods; Minerals; Modeling; Mus; Mutant Strains Mice; Mutation; N-terminal; Osteomalacia; Paraneoplastic Syndromes; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Phenocopy; Phenotype; Play; Process; Production; Protein Isoforms; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Resistance; Role; Role playing therapy; Serum; Signal Pathway; Signal Transduction; Site; Specificity; Structure; Syndrome; Testing; Tissues; Translating; Tyrosine Kinase Domain; X-Ray Crystallography; bone; cell motility; gain of function; human disease; in vivo; inhibitor/antagonist; inorganic phosphate; loss of function; member; mouse model; mutant; novel; novel strategies; receptor; response; small molecule; three dimensional structure; tumor; wasting

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.

FGF通过与受体酪氨酸激酶的结合和激活来介导其生物学反应 （RTK）由四种指定的FGFR1-FGFR4组成。 FGFR 1-3产生了两个同工型 通过交替的剪接，其配体结合特异性和组织表达模式有所不同。 FGF23是22个已知FGF中最大的FGF，与其他FGF之间的独特C末端不同 领域。 X连锁的下磷酸rike（XLH）患者的FGF23水平升高，并且 FGF23基因中蛋白酶识别位点内的杂合突变引起综合征 表XLH，常染色体显性次磷酸ri鼠（ADHR）。在ADHR中，对 FGF23分子的蛋白水解切割大概会导致清除率延迟和积累 循环。此外，肿瘤诱导骨质乳酸（TIO），另一种与表型相似的疾病 XLH已被发现在许多情况下是由于肿瘤过量生产FGF23作为副塑料引起的 综合征。最后，导致循环低下FGF23水平的隐性突变会导致肿瘤 钙化病（TC），一种异常疾病，其中血清P水平升高。因此这些临床观察 在磷酸盐稳态中尤其是FGFS，尤其是FGF23的新作用。但是，几乎没有 了解FGF23的作用方式，以及转换新信息的潜力 这些通往人类疾病的途径很棒。 因此，该项目的总体目标是（1）通过FGF确定FGF23的细胞信号传导函数 受体，（2）确定FGF23的原子结构，（3）探索FGF23的受体特异性 使用缺乏特定FGFR同工型的鼠模型（4）生成新的鼠标模型来探索 FGF23在正常和疾病条件下的生物学功能，以及（5）开发新药理 使用FGFR酪氨酸激酶结构域的小分子抑制剂治疗疾病的方法 由FGF23功能异常引起。我们的目标将通过应用遗传，生化， 结构和细胞生物学方法，在模型的人类疾病的环境中 随后的翻译应用。