P3: The Structure, Function, and Pharmacologic inhibition of FGF23
P3: The Structure, Function, and Pharmacologic inhibition of FGF23
批准号:
7684865
负责人:
JOSEPH SCHLESSINGER
金额:
$37.64万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2008
资助国家:
美国
项目状态:
已结题
起止时间:
2008-09-01 至 2011-08-31
关键词:
AdultAlternative SplicingAnimal ModelApplied GeneticsBindingBiochemicalBiologicalBiological ProcessBlood CirculationC-terminalCalcinosisCellsClinicalComplexConditionDiseaseDockingDrug or chemical Tissue DistributionEmbryonic DevelopmentEndocrineEndopeptidasesFamilial hypophosphatemic bone diseaseFamilyFibroblast Growth FactorFibroblast Growth Factor Receptor 2Fibroblast Growth Factor ReceptorsGenesGeneticGenetically Engineered MouseGoalsHeparan Sulfate ProteoglycanHeparinHomeostasisIn VitroInterventionKnock-in MouseKnockout MiceLifeLigand BindingMediatingMethodsMineralsModelingMusMutant Strains MiceMutationN-terminalOsteomalaciaParaneoplastic SyndromesPathway interactionsPatientsPatternPeptide HydrolasesPhenocopyPhenotypePlayProcessProductionProtein IsoformsProtein Tyrosine KinaseProteinsReceptor Protein-Tyrosine KinasesResistanceRoleRole playing therapySerumSignal PathwaySignal TransductionSiteSpecificityStructureSyndromeTestingTissuesTranslatingTyrosine Kinase DomainX-Ray Crystallographybonecell motilitygain of functionhuman diseasein vivoinhibitor/antagonistinorganic phosphateloss of functionmembermouse modelmutantnovelnovel strategiesreceptorresponsesmall moleculethree dimensional structuretumorwasting
中文摘要
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FGFR 1-FGFR 4。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。
FGF 23是已知的22种FGF中最大的一种,其独特的C末端延伸不同于其他FGF。
域X连锁低磷血症性佝偻病(XLH)患者循环中FGF 23水平升高,
FGF 23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,
FGF 23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FGF 23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FGF 23的原子结构;(3)探讨FGF 23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,
FGF 23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
FGF 23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。
英文摘要
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.
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会议论文
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