FMRP AND mRNA TRANSLATION

描述：脆性X综合征是由于缺乏功能性 由FMR 1基因编码的蛋白产物，命名为FMRP。虽然 FMRP的确切功能仍有待确定，积累的证据支持 FMRP是信使核糖核蛋白（mRNP）的概念， 选择性地与翻译多聚核糖体通过多聚-A RNA在生活 细胞FMRP-多聚核糖体缔合和mRNP的功能重要性 1304 N点的存在表明了复合物的形成 从一个异常严重的脆性X患者中发现的突变， FMRP掺入到不能与FMRP结合的异常mRNP颗粒中 多核糖体这些观察结果使申请人假设， FMRP与mRNP复合物和对照内的mRNA靶点相互作用 这些mRNA的翻译活性。这一假设得到了 申请人？最近发现FMRP在体外以剂量依赖性抑制翻译， 和mRNA选择性的方式。 该提案旨在进一步测试上述假设，使用体外 翻译系统、培养的细胞系以及野生型和FMRL 通过以下三个具体目的敲除神经元：1）.测试 假设FMRP作为翻译抑制剂的选择性， 兔网织红细胞裂解物（RRL）通过FMRP结合活性测定， 翻译模板; 2）.为了阐明可能的机制， FMRP引起的体外翻译抑制;为了验证这个假设， FMRP抑制活细胞中的翻译，并且细胞外信号调节 FMRP？对翻译的影响。 拟议的研究将解决FMRP如何影响翻译， 无论是FMRP？的影响，翻译可以调节，以适应细胞 功能这些问题的答案将大大提高我们对 FMRP？的功能，这不仅有利于阐明 脆性X综合征的发病机制，但更重要的是有助于了解 RNA-蛋白质相互作用如何调节翻译以影响大脑功能 发展先行者的要求

Description: Fragile X syndrome is caused by the lack of the functional protein product encoded by the FMR1 gene, designated as FMRP. Although the exact function of FMRP remains to be defined, accumulating evidence supports the concept that FMRP is a messenger-ribonucleoprotein (mRNP), which selectively associates with translating polyribosomes via poly-A RNA in living cells. The functional importance of FMRP-polyribosome association and mRNP complex formation has been indicated by the fact that the 1304N point mutation, identified from an unusually severe fragile X patient, causes incorporation of FMRP into abnormal mRNP particles that fail to associate with polyribosomes. These observations have led the applicant to hypothesize that FMRP interacts with its mRNA targets within the mRNP complexes and controls the translation activity of these mRNAs. This hypothesis is reinforced by the applicant?s recent finding that FMRP inhibits translation in vitro in a dose-dependent and mRNA-selective manner. This proposal aims to further test the above hypothesis using in vitro translation systems, cultured cell lines, as well as wild type and fmrl knockout neurons by the following three specific aims: 1). To test the hypothesis that the selectivity of FMRP as a translation suppresser in the rabbit reticulocyte lysate (RRL) is determined by the FMRP-binding activity of the translation templates; 2). To elucidate possible mechanisms for the in vitro translation inhibition caused by FMRP; 3). To test the hypothesis that FMRP inhibits translation in living cells, and extracellular signals modulates FMRP?s influence on translation. The proposed research will address how FMRP may influence translation, and whether FMRP?s influence on translation can be regulated to accommodate cell function. Answers to these questions should greatly improve our knowledge on FMRP?s function, which not only facilitates the elucidation of the pathogenesis of fragile X syndrome, but more importantly helps to understand how RNA-protein interactions may regulate translation to impact brain function and development.