FMRP AND mRNA TRANSLATION

描述：脆性X综合征是由于缺乏功能性 由FMR1基因编码的蛋白质产物，指定为FMRP。尽管 FMRP的确切功能有待确定，越来越多的证据支持 FMRP是信使-核糖核蛋白(MRNP)的概念，它 在活体中通过聚A RNA选择性地与翻译多核糖体结合 细胞。FMRP-多聚核糖体结合和mRNP的功能重要性 1304N点的事实表明了复杂的形成 从一名异常严重的脆性X患者身上发现的突变会导致 将FMRP掺入未能结合的异常mRNP颗粒中 多聚核糖体。这些观察结果使申请人假设 FMRP在mRNP复合体和对照中与其mRNA靶点相互作用 这些mRNAs的翻译活动。这一假设得到了以下结论的强化 申请人S最近发现FMRP以剂量依赖的方式抑制体外翻译 和mRNA选择性方式。 该建议旨在通过体外实验进一步验证上述假设。 翻译系统、培养的细胞系以及野生型和fmrl 通过以下三个特定目的敲除神经元：1)。要测试 假设FMRP在翻译中作为翻译抑制因子的选择性 兔网织红细胞裂解物(RRL)由FMRP结合活性决定 翻译模板；2)。阐明In的可能机制 3)FMRP对体外翻译的抑制作用。来检验这一假设 FMRP抑制活细胞内的翻译，细胞外信号调节 FMRP？S对翻译的影响。 拟议的研究将解决FMRP如何影响翻译，以及 FMRP、S对翻译的影响是否可以调节以适应细胞 功能。这些问题的答案应该会大大提高我们对 FMRP？S功能，这不仅有助于阐明 脆性X综合征的发病机制，但更重要的是有助于理解 RNA-蛋白质相互作用如何调节翻译影响大脑功能 和发展。

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.