PICK1在脑内氧化应激损伤中的作用及其机制研究

项目名称： PICK1在脑内氧化应激损伤中的作用及其机制研究

项目编号： No.31460257

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 神经、认识与心理学

项目作者： 李云鸿

作者单位： 宁夏医科大学

项目金额： 48万元

中文摘要： 氧化应激损伤造成的神经细胞凋亡是导致神经系统疾病的重要因素。谷胱甘肽GSH对维持脑内氧化还原平衡至关重要，而谷氨酸转运体EAAC1对神经元摄取半胱氨酸从而合成GSH又起着决定性作用，但是EAAC1的调节机制研究还非常欠缺。支架蛋白PICK1具有多种生物学功能，在突触可塑性和一些疾病中发挥着重要作用，但未见其在氧化应激中作用的报道。我们首次发现，PICK1敲除小鼠脑内GSH减少，氧化损伤指标nitrotyrosine和4-HNE显著升高，提示PICK1缺失导致了氧化应激反应。PICK1可以和EAAC1免疫共沉淀，提示在抗氧化应激反应中PICK1可能起到调控EAAC1的作用。本项目将在前期基础上，利用PICK1基因敲除模型和氧化损伤小鼠模型，结合western blot、细胞免疫荧光、神经元和脑片原代培养、电生理等技术，研究PICK1调节神经元氧化损伤的机制，为氧化应激相关疾病的治疗提供新靶点

中文关键词： 氧化应激；谷胱甘肽；PICK1；EAAC1；神经元

英文摘要： The oxidative stress caused neuron apoptosis is an important factor in several neurologic disorders. Studies show that glutathione (GSH) plays a pivotal role in maintaining the balance of oxidation-reduction equilibrium in brain, and EAAC1 plays a decisive role in GSH synthesis by uptake cysteine. The study on the mechanism of EAAC1 is rare. The supporting protein PICK1 has multiple biological functions and associated with many major diseases. However, the role of PICK1 in oxidative stress is unclear. Our preliminary data first showed that PICK1 knockout could lead to oxidative stress by decreasing the anti-oxidative injury marker GSH level and increasing the oxidative injury marker Nitrotyrosine and 4-HNE levels indicating that PICK1 knockout could cause the oxidative stress. PICK1 could coimmunoprecipitated with EAAC1 indicating that PICK1 might regulate EAAC1 in the oxidative stress. In this project, we will continue to study how PICK1 regulates the oxidative stress in CNS using combined techniques from both in vivo and in vitro, including gene knockout mice model and oxidative injury mice model , western blot, immunocytochemistry, neuron primary culture. This project will reveal the regulatory mechanisms of PICK1 on the oxidative stress and provide new potential treatment target for the oxidative stress related diseases.

英文关键词： oxidative stress;glutathione;PICK1;EAAC1;neuron