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通过结合并激活受体酪氨酸激酶家族介导其生物学反应 RTKs由四种基因产物组成，命名为FGFR1-FGFR4。FGFR 1 - 3具有产生的两种同种型 通过在其配体结合特异性和组织表达模式上不同的选择性剪接。 FGF23是已知的22种FGFs中最大的一种，与其他FGFs的不同之处在于其独特的延伸C末端 域X连锁低磷血症性佝偻病（XLH）患者循环中FGF 23水平升高， FGF23基因中蛋白酶识别位点内的杂合突变引起一种综合征， 表型XLH，常染色体显性低磷血症性佝偻病（ADHR）。在ADHR中， FGF23分子的蛋白水解裂解可能导致延迟的清除和在细胞中的积累。 流通此外，肿瘤诱导的骨软化症（TIO），另一种具有类似表型的疾病， XLH，已发现在许多情况下是由作为副肿瘤因子的FGF 23的肿瘤过度产生引起的。 综合征最后，隐性突变导致低的完整循环FGF 23水平，导致肿瘤生长抑制。 钙质沉着症（TC），一种血清P水平升高的不常见疾病。因此，这些临床观察 认为FGF，特别是FGF 23在磷酸盐稳态中具有新的作用。然而， 了解FGF23的作用方式，以及从探索中翻译新信息的潜力。 这些导致人类疾病的途径是非常重要的。 因此，本课题的总体目标是：（1）确定FGF 23通过FGF介导的细胞信号传导功能 （2）确定FGF23的原子结构;（3）探讨FGF23的受体特异性 使用缺乏特异性FGFR同种型的小鼠模型，（4）为了产生新的小鼠模型以探索FGFR的表达， FGF23在正常和疾病状态下的生物学功能，以及（5）开发新的药理学活性。 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 FGF23功能异常引起的。我们的目标将通过应用遗传学，生物化学， 结构和细胞生物学方法，在人类疾病模型的设置中， 随后的翻译应用。