磷脂酰肌醇3,5二磷酸(PI(3,5)P2)是近年来发现一种重要的信号磷脂分子，由Fab1/PIKfyve-Vac14-Fig4/Sac3复合物合成。我们在基因敲除小鼠中的研究表明，PI(3,5)P2的缺失导致小鼠神经系统的退行性病变。PI(3,5)P2通路相关的基因突变也是多种人类神经系统遗传疾病的基础。因此，研究PI(3,5)P2通路的调控及其神经保护作用有着重要的理论意义和实用价值。在本项目中，我们拟首先利用我们发现的高活性PIKfyve激酶上调PI(3,5)P2，并检测高PI(3,5)P2水平在兴奋性毒性过程中的神经保护作用。其次，我们将用免疫共沉淀-质谱的方法寻找与Fab1/PIKfyve相互作用的蛋白，阐明PI(3,5)P2的关键调控机制，以期获得可作为新治疗靶点的分子，建立新的有效的神经退行性疾病治疗方法。

The low abundance signaling lipid phosphatidylinositol(3,5)-bisphosphate (PI(3,5)P2) has recently been identified as an important signaling lipid. It is synthesized and regulated by a protein complex composed of Fab1/PIKfyve, Vac14, and Fig4. Mice hypomorphic for Vac14 and Fig4 show massive degeneration in the central and peripheral nervous systems. Mutations in human Fig4 have been implicated in Charcot-Marie-Tooth syndrome and Amyotrophic Lateral Sclerosis. Vac14, Fig4 and Fab1 are present in all tissues, suggesting that PI(3,5)P2 functions in all organs, yet is particularly crucial in neural tissues. Here we plan to use hyperactive PIKfyve kinase developed by us to elevate PI(3,5)P2 levels and examine its neuroprotective effects. In addition, we will use immunoprecipitation and mass spectrometry to identify regulator or effector proteins in this pathway. New players in this pathway will provide promising targets for treating acute brain trauma or chronic neurodegenerative diseases.