环氧脂肪酸8,9-EET负向调控“TLR7-IL-6”轴改善草甘膦诱导孤独症的机制研究

中枢神经系统炎症在孤独症谱系障碍（ASD）中发挥重要作用，IL-6是已知的能够影响神经元突触功能的关键炎症介质。环氧脂肪酸是一类具有较强抗炎能力的脂质，但易被环氧化物水解酶（sEH）水解。申请人前期研究首次建立了草甘膦诱导的ASD模型，并发现抑制子鼠大脑中高表达的sEH可逆转显著下降的环氧脂肪酸8,9-EET。体内实验及测序结果显示补充8,9-EET能够有效改善ASD样行为，其机制可能与TLR7下调有关。本课题旨在探索8,9-EET负向调节草甘膦诱导ASD的作用及分子机制，拟结合体内外实验、采用基因敲除动物，细胞转染/沉默等分子生物学实验手段，阐明8,9-EET是否通过抑制“TLR7/MyD88/NF-κB-IL-6”轴, 发挥维持神经元细胞稳态及改善草甘膦诱导ASD的作用。该项目的实施将为中枢神经系统炎症在ASD发病机制中的认知以及ASD治疗新靶点的探究提供理论依据。

Inflammation in central nervous system is believed to play an important role in autism spectrum disorder (ASD), and IL-6 make a major contribution in affecting synaptic functions. Epoxy fatty acids are a class of lipids with strong anti-inflammatory properties, but they are easily hydrolyzed by soluble epoxide hydrolase (sEH). Our previous study found maternal glyphosate exposure cause ASD-like behavior in offspring and inhibiting the high expression of sEH can significantly increase epoxy fatty acid 8,9-EET in the brains of offspring. In vivo and gene sequencing results show that treatment with 8,9-EET significantly ameliorated ASD-like behavior of juvenile offspring after maternal glyphosate exposure and it may be related to the downregulation of TLR7. This project intends to combine in vivo and in vitro experiments, by using gene knockout mice, cell transfection/silencing and other molecular biology experimental methods to clarify the role of 8,9-EET in maternal glyphosate exposure-induced ASD through inhibiting the "TLR7/MyD88/NF-κB-IL-6" axis. This project will provide a new cognition of inflammation in ASD and will be helpful for the new strategies and methods of ASD therapy.