Parkin-NLRP3负反馈调控环路在鱼藤酮诱导神经元退变中的作用及机制研究

鱼藤酮是应用广泛的杀虫剂，可引起神经元退变，导致帕金森病（PD），但其致病机制尚不明确。E3泛素连接酶Parkin对维持神经元稳态至关重要，而炎症小体NLRP3是驱动炎症反应的核心因素。前期研究证实Parkin与PD发生发展密切相关。预实验发现鱼藤酮导致Parkin活力下降和炎症小体NLRP3活化，且Parkin与NLRP3可相互影响，提示鱼藤酮诱导PD致病过程可能存在Parkin-NLRP3负反馈调控环路。本项目拟在转基因小鼠，采用激光共聚焦显微镜等方法观察Parkin-NLRP3负反馈调控环路的分子变化；在细胞模型，利用干扰、过表达等分子生物学技术，iTRAQ和RNA-seq等组学技术，探讨Parkin降解NLRP3和NLRP3抑制Parkin活力的调控机理。项目将阐明鱼藤酮引起的Parkin-NLRP3负反馈调控环路在神经元退变中的作用机制，为鱼藤酮诱导PD的防治提供新思路。

Rotenone is one of the most widely used pesticides，which can cause neuronal degeneration, increase the incidence rate of Parkinson's disease (PD). However, its pathogenesis remains unclear. Parkin is known to be essential for maintaining neuronal homeostasis, and NLRP3 is the core factor driving the inflammatory response. In previous studies, we reported that E3 ubiquitin ligase Parkin is closely related to the occurrence and development of PD.The applicant found that the decrease of Parkin enzyme activity was accompanied by abnormal activation of NLRP3 and that Parkin- NLRP3 could influence each other in rotenone-induced PD models, which suggests that there may be a Parkin-NLRP3 negative feedback loop in this modes. In this project, we intends to detect the molecular changes of Parkin-NLRP3 negative feedback loop in transgenic mice. In vitro, molecular biology techniques and omics techniques indcuding iTRAQ and RNA seq were used to explore the mechanism that NLRP3 regulated by Parkin and that NLRP3blocks parkin activity. The aim of this study was to elucidate the mechanism of Parkin-NLRP3 negative feedback loop in rotenone-induced neuronal degeneration, and provide a new idea for the prevention and treatment of rotenone induced PD.