代谢酶依赖的丙烯酰胺神经突触可塑性损伤效应研究

Synapse, which maintains normal physiological regulation and coordination of other systems, is the structural and functional basis of chemical and electrophysiological signal transmission in the nervous system. Synaptic pathological damage is a key step during the process of neurotoxicity. Our previous work studied the functions of synapsin I in phosphorylation cascade signaling pathway, conformational change and SNARE complex receptors combination/ dissociation, and determined the existence of synaptic plasticity effect chain. The objective of this project which based on the theory of synaptic plasticity and the effect of CYP2E1 on neurotoxic effect is to clarify the relationship between ACR presynaptic plasticity and postsynaptic plasticity, and build and verify the hypothesis of ACR-CYP2E1-GA: Ca2+-GAP-43- synapsinI:SNARE-Ca2+- ATPase/Na+-K+-ATPase- PSD-95-NMDAR-CaMKII effect chain. Except that, this project will analysis the feasibility of functional protein as a biomarker, clarify the mechanism of neurotoxic effect under the actual metabolic conditions, and establish a complete chemical signal transduction pathway of synaptic plasticity which might provide a theoretical and technical support for the prevention of ACR-induced nervous damage.

突触系神经系统化学和电生理信号传递的结构和功能基础，维持机体其它系统正常生理的调节，其病理性损伤构成神经毒效应发生的中心环节。本课题组的前期研究揭示了以功能蛋白突触素I为中心的磷酸化级联反应信号传导通路、突触素I构象变化及SNARE复合体结合/解离状态的作用，确定了突触可塑性损伤效应的客观存在。本项目依托突触可塑性理论，基于毒物代谢酶CYP2E1的起始点效应及对神经毒效应机制的影响，阐明ACR突触前可塑性与突触后可塑性之间的关联，构建ACR-CYP2E1-GA: Ca2+-GAP-43- synapsinI:SNARE-Ca2+-ATPase/Na+-K+-ATPase-PSD-95-NMDAR-CaMKII损伤效应假说并加以验证，分析功能蛋白作为生物标志的可行性，阐明实际代谢条件下神经毒效应的发生发展机制，构建突触可塑性的完整化学信号转导路径，为ACR神经损伤的防治提供理论和技术支撑。

本项目依托突触可塑性理论和本课题组的前期研究结果，基于毒物代谢酶CYP2E1的起始点效应及对神经毒效应机制的影响，通过构建代谢酶依赖的ACR突触可塑性损伤效应细胞模型（神经元-肝细胞共培养）和大鼠神经突触损伤模型，阐明ACR突触前后可塑性间的关联，构建ACR-CYP2E1-GA: Ca2+-GAP-43-synapsinI:SNARE- Ca2+-ATPase/Na+-K+-ATPase-PSD-95-NMDAR-CaMKII损伤效应假说，并在通过重点人群（ACR典型暴露作业工人、非ACR暴露作业工人）进行验证，细胞和实验动物层面的研究结果提示，ACR主要代谢产物GA发挥着重要的神经损伤作用，从而为最终有效阐明实际代谢条件下神经毒效应的发生发展机制提供重要的数据线索，为ACR神经损伤的防治提供理论和技术支撑。