慢性谷氨酸兴奋毒性是神经退行性病变过程中神经细胞损伤的重要病理机制之一。预实验发现，低于突触外浓度的谷氨酸长时间刺激神经元和星形胶质细胞可改变CYPs表达水平，且谷氨酸受体拮抗剂能减弱其调控作用。文献和预实验表明，脑CYPs参与神经细胞膜脂类物质代谢。然而，脑CYPs表达亚型、底物催化功能和表达调控机制与肝脏组织存在明显差异，神经细胞膜脂代谢网络可能与外周迥然不同。本研究拟以谷氨酸为代表，通过阐明谷氨酸受体偶联信号转导通路调控脑CYPs表达的分子机制，揭示神经递质参与调控内源性物质代谢的生物学功能；利用RNAi干扰技术和基因敲除动物，确定神经细胞膜脂类物质的CYPs依赖性代谢物种类及脑区分布特点；利用慢性谷氨酸兴奋毒性动物模型，观察膜脂类物质CYPs代谢路径的变化特征。研究数据将有助于从代谢角度深入认识慢性谷氨酸兴奋毒性致神经细胞损伤的病理机制，为多靶点干预谷氨酸兴奋毒性提供新的思路。

Chronic glutamate excitotoxicity is one of the important pathological mechanisms of the damage to neural cells in neurodegenerative disease. In the pilot studies, we found that CYPs levels in neurons and astrocytes were regulated by long-term glutamate treatment at the concentration lower than the extrasynaptic concentration, and that the antagonists of glutamate receptor can attenuate the changes in CYPs levels. The literatures and our previous work have shown the differences in the expression, catalytic function and regulation between brain and hepatic CYPs. Thus, the metabolic network of membrane lipids of the neural cells in brain can be very different from the peripheral network. In the present study, we try to reveal the biological function of neurotransmitters in the regulation of the endogenous substance metabolism. The regulation mechanism of brain CYPs by glutamate receptor-coupled signal transduction pathways will be elucidated. We will identify the CYPs-dependent metabolites from membrane lipids and the distribution among brain regions using RNA interference technique and knockout mice. And the changes in the CYPs-dependent metabolism of membrane lipids induced by chronic glutamate excitotoxicity will be characterized. The data will expand our knowledge of the pathological mechanism of the damage to the neural cells induced by chronic glutamate excitotoxicity from the metabolic point of view, and may provide the new clue for the multi-target interventions of glutamate excitotoxicity.