智力障碍相关蛋白PQBP1通过调控eEF2磷酸化介导蛋白质翻译的机制研究

X连锁智力发育障碍致病基因多聚谷氨酰胺结合蛋白1（PQBP1）在神经系统中高表达并且在发育过程中受到严格的时空调控，提示它在神经发育和认知功能中起重要作用，但我们对它的生理功能和致病机理还缺乏了解。我们在最近发表的论文中揭示了PQBP1在果蝇感光细胞中与核糖体结合调节特定基因表达的分子机理，证实了这种分子功能在哺乳动物中是保守的。并且通过进一步实验我们发现PQBP1能结合翻译延伸因子eEF2并影响eEF2的磷酸化水平。为了了解其中详细的机制和生理意义，本项目首先将通过生化分析明确PQBP1结合eEF2并调节其磷酸化的分子机制，接着通过转录组和蛋白组学解析受PQBP1/eEF2调控的下游蛋白网络，并研究神经活动对PQBP1/eEF2相互作用的影响，最后利用小鼠模型探索PQBP1/eEF2调控蛋白质翻译在神经生理活动中的影响。这些研究将帮助我们了解PQBP1的功能和导致智力发育障碍的机理。

X-linked intellectual disability-causing gene polygluatmine binding protein 1(PQBP1) is highly expressed in nervous system under strict spatiotemporal control, which underlines its importance in neurodevelopment and cognitive functions. But the physiological functions and pathogenesis of PQBP1 are still poorly understood. We reported in our recent article that Drosophila PQBP1 bound the ribosome and regulated the expression of a specific set of mRNAs, a conserved molecular function also found in mammals. Our further investigation revealed that PQBP1 interacted with eEF2 and regulated its phosphorylation. In order to elucidate the detailed mechanism, we propose to use sophisticated biochemical approaches, transcriptomic and proteomic analysis, cell biology and electrophysiology to study how PQBP1 regulates eEF2 phosphorylation and what is the physiological significance of this interaction. These investigations will greatly improve our understandings of PQBP1 functions and pathogenesis.