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

P3：FGF23 的结构、功能和药理学抑制

基本信息

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
项目类别：
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

项目摘要

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来介导其生物反应（RTK）由命名为 FGFR1-FGFR4 的四种基因产物组成。 FGFR 1-3 产生两种亚型通过其配体结合特异性和组织表达模式不同的交替剪接。 FGF23 是 22 种已知 FGF 中最大的一种，其独特的扩展 C 端与其他 FGF 不同领域。 X 连锁低磷血症性佝偻病 (XLH) 患者的 FGF23 循环水平升高，并且 FGF23 基因蛋白酶识别位点内的杂合突变会导致一种综合征，表型 XLH，常染色体显性低磷血症性佝偻病 (ADHR)。在 ADHR 中，抵抗 FGF23 分子的蛋白水解裂解可能导致清除和积聚延迟循环。此外，肿瘤诱发的骨软化症（TIO）是另一种与骨软化症具有相似表型的疾病。 XLH，已发现在许多情况下是由肿瘤过度产生 FGF23（作为副肿瘤细胞）引起的综合症。最后，隐性突变导致完整循环 FGF23 水平较低，从而导致肿瘤钙质沉着症 (TC)，一种血清磷水平升高的罕见疾病。因此，这些临床观察认为 FGF（尤其是 FGF23）在磷酸盐稳态中具有新的作用。然而，很少的是了解 FGF23 的作用模式，以及通过探索转化新信息的潜力这些通往人类疾病的途径是伟大的。因此，该项目的总体目标是（1）通过FGF确定FGF23的细胞信号传导功能受体，(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 同工型的小鼠模型，(4) 生成新的小鼠模型来探索 FGF23在正常和疾病条件下的生物学功能，以及（5）开发新的药理学使用 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，在人类疾病模型的背景下发扬光大后续翻译应用。