Nrf2和NF-κB的crosstalk介导丙烯酰胺对多巴胺能神经元的损伤及机制的研究

Acrylamide (ACR)is a well-known neurotoxin and is very harmful to human beings, but its mechanism is not fully understood. This current project is designed to investigate the adverse effects of ROS evoked by ACR on the striatal dopaminergic neuron and signal pathways both in vivo and in vitro . Two intracelluar signal pathways ，Nrf2 and NF-κB and even their crosstalk are involved. The striatal dopaminergic neurons play an important role in the regulation system of somatic motor,sensory and learning memory. Keap-1/Nrf2/ARE/antixidant pathway is a celluar protective mechanism in the cell while IκB-NF-κB/IRE/inflammation pathway is considered as a celludar damage pathway.The hypothesis of the current project is ,on the early stage of ACR toxiciy, ROS induced by ACR can activate both the Nrf2 and NF-κ B pathways ,thus the balance is maintained. With the development of the toxicity, especially with the crosstalk between the two pathways, the activation of Nrf2 is inhibited，and the balance is broken，thereby leading to cell general damage.The two pathwys are investigated respectively in vivo, and the crosstalk between Nrf2 and NF-κ B pathways is conducted only in vitro.With siRNA cellular transfection technique to inhibit one pathway ,or with specific agonist to induce one pathway, the effect of ACR on the other pathway and the celluar responses are detected.The current research will contribute to fully understand the mechanism of ACR and to explore the new preventive and control stratey against ACR.

丙烯酰胺（ACR ）是一种确认的人类神经毒物，但其毒作用机制仍不十分明了。现有研究表明氧化应激参与ACR神经毒性作用，但ACR能否通过ROS激活细胞内信号通路的变化目前尚未见报导。ROS能诱发转录因子Nrf2和NF-κB的活化，Nrf2调节的下游基因为抗氧化酶和Ⅱ相代谢酶基因，是一种细胞保护性机制， NF-κB信号通路能激活机体的炎性反应，在神经细胞中是一种细胞损伤机制，Nrf2和 NF-κB之间能够通过crosstalk相互影响。本研究拟以ACR引起的多巴胺能神经元氧化应激为切入点，以细胞内Nrf2和NF-κB信号通路为轴线，利用整体动物和体外细胞实验模型，应用神经生物学，细胞分子生物学方法，siRNA技术研究Nrf2和NF-κB信号通路以及他们之间的crosstalk在ACR神经毒性中的作用。本项目能为进一步阐明ACR的毒作用机制，为研发ACR中毒的防治策略奠定理论基础

丙烯酰胺（ACR ）是一种z轴索毒物，但其毒作用机制仍不十分明了。现有研究表明氧化应激参与ACR神经毒性作用，ROS能诱发转录因子Nrf2和NF-κB的活化，Nrf2调节的下游基因为抗氧化酶和Ⅱ相代谢酶基因，是一种细胞保护性机制， NF-κB信号通路能激活机体的炎性反应，在神经细胞中是一种细胞损伤机制，Nrf2和 NF-κB之间能够通过crosstalk相互影响。本研究利用整体动物和体外细胞实验模型，应用神经生物学，细胞分子生物学方法，siRNA技术研究Nrf2和NF-κB信号通路以及他们之间的crosstalk在ACR神经毒性中的作用。研究结果表明，ACR灌胃和脑室注射途径均能影响纹状体多巴胺能神经元，造成氧化损伤和炎性反应以及凋亡。同时激活机体MAPK,Nrf2和 NF-κB信号通路。细胞研究表明，MAPK能调节Nrf2和 NF-κB的激活，Nrf2和 NF-κB之间可以相互调节。线粒体凋亡是细胞凋亡的主要途径。抑制JNK和P38能减轻ACR导致的凋亡。Nrf2的激活是集体代偿性的保护作用。而NF-κB的激活介导了前炎症因子的释放，本项目能j加深对ACR神经毒性的认识，为防治ACR中毒提供分子靶点。