与膀胱癌相关联的FGFR3b功能获得性突变体结构解析及致病机制研究

项目名称： 与膀胱癌相关联的FGFR3b功能获得性突变体结构解析及致病机制研究

项目编号： No.31270789

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 陈怀彬

作者单位： 温州医科大学

项目金额： 80万元

中文摘要： 膀胱癌的发生与发展与成纤维细胞生长因子受体3b(FGFR3b)的功能获得性突变存在紧密的内在联系，因此FGFR3b已经成为膀胱癌治疗重要的潜在靶点。但是，FGFR3b功能获得性突变致病的内在分子机制尚未被揭示，而且由于缺乏对FGFR3b在分子/结构层面的认识，针对FGFR3的特异性肿瘤抑制剂均处于前期探索阶段。基于此，本课题将重点运用结构生物学的研究手段解析野生和功能获得性突变的FGFR3b胞外结构域和胞内激酶结构域晶体结构，并结合生物化学、生物物理学的研究方法，从分子层面阐明膀胱癌中FGFR3b功能获得性突变引起致癌性激活的机理。本课题的实施将加深人们对FGFR3b异常突变与膀胱癌发生发展内在关联机制的认识，同时将会为针对FGFR3靶点的特异性膀胱癌抑制剂的开发提供直观的结构模型和设计指导。

中文关键词： 成纤维细胞生长因子受体3；功能获得性突变体；结构解析；膀胱癌；致病机制

英文摘要： There is increasing evidence that upregulated Fibroblast Growth Factor (FGF) signaling due to gain-of-function mutations found in FGF Receptor 3b (FGFR3b) contribute to the occurrence and development of bladder cancer. Consequently, FGFR3b has become a very important potential drug discovery target for bladder cancer therapeutics. However, the underlying pathogenic mechanism of those gain-of-function FGFR3b mutations has eluded explanation. Due to the lack of structural/molecular understanding of FGFR3b, current study for the development of specific bladder cancer inhibitor is mostly in its infancy. In this proposed study, by using X-ray crystallography coupled with Mass Spectrometry, SPR, ITC and other biochemical and biophysical methods, we will determine the crystal structures of the extracellular domain and kinase domain of wild-type and gain-of-function mutant FGFR3bs; and elucidate the molecular mechanism by which gain-of-function FGFR3 mutations lead to bladder cancer. The fundamental structural and biochemical information obtained from this study will greatly enhance our knowledge of the intrinsic association between the bladder cancer and the pathogenic FGFR3b mutations, and will provide the direct structural model for and facilitate the rational design of novel inhibitor for specific use in treatment o

英文关键词： FGFR3b；gain-of-function mutations；structural analysis；bladder cancer；pathogenic mechanism