三邻甲苯基磷酸酯（TOCP）用途极为广泛，其诱发的迟发性神经毒性机制一直未能完全阐明。近年研究发现“自噬”在TOCP引起的神经毒性中起作用，但其调节机制不清楚。基于我们前期发现TOCP影响calpain、PKC、泛素蛋白酶体活性等工作基础，本项目以TOCP诱发实验鸡迟发性神经毒性模型，观察毒性效应过程中细胞钙紊乱及钙相关信号分子、骨架蛋白磷酸化与泛素化、自噬受体蛋白的动态变化，同时结合细胞模型，明确钙紊乱与TOCP诱发自噬改变的关系。在此基础上，通过应用一系列工具药物（激活剂、抑制剂）、RNA干涉及诱导分化等策略深入研究calpain、PKC和IP3R等钙信号相关分子和自噬受体蛋白在TOCP所致神经细胞自噬中的调节作用与机制。研究结果从新的角度去探索TOCP神经毒性相关机制，不仅有助于拓宽对TOCP诱发的迟发性神经毒性机制的认识，而且对于进一步研究新的干预策略亦有一定的参考价值。

Tri-ortho-cresyl phosphate (TOCP) is widely used, and the mechanism of its delayed neurotoxicity has not been fully clarified. In recent years, some studies found that autophagy plays an impotant role in the neurotoxicity induced by TOCP, but the regulation mechanism is not clear. Based on our previous studies and founds of TOCP affecting the activities of calpain, PKC and ubiquitin-proteasome, in this project, we will build a delayed- neurotoxicity mode of hens induced by TOCP to observe cell calcium homeostasis, and the dynamic changes of calcium-related signaling molecules, the phosphorylation and ubiquitination of some related cytoskeletal proteins, and the expression of autophagy receptor proteins.Meanwhile, combining with the cell model, we will pinpoint the relationship between the disorder of calcium and change of autophagy induced by TOCP. On this basis, we will also do further research of calpain,PKC, IP3R, calcium signaling related molecules and autophagy receptor protein on the regulating autophagy induced by TOCP by using a series of tool drugs(activators and inhibitors), RNA interference and nerve cell differentiation strategy. The results demonstrate the neurotoxicity mechanism of TOCP,not only broaden the knowledge of delayed neurotoxicity of TOCP, but also contributed to further study the new intervention strategies for neurodegenerative diseases.