孤独症谱系障碍（ASD）是一种严重的神经发育障碍性疾病。研究表明肥胖可加重ASD模型鼠的认知及社交损伤。本课题组前期针对同卵双生非共患ASD的表观遗传学研究发现，肥胖主效基因SH2B1的甲基化水平存在明显差异，提示该基因与ASD有一定关联。本项目以ASD患儿及所构建的Sh2b1缺失的BTBR孤独症模型鼠为研究对象，明确肥胖及肥胖主效基因SH2B1对ASD认知及社交行为的影响；应用ASD人源性iPSCs和BTBR+Sh2b1-/-模型鼠来源的神经元共同探讨SH2B1是否介导IGF-1R信号通路造成ASD神经元功能损伤及凋亡；此外，采用膜片钳技术，阐明SH2B1基因参与IGF-1R对神经元Kv钾通道的调控以及下游信号转导通路PI3K/AKT/mTOR在其中的作用，从细胞和分子水平揭示肥胖主效基因SH2B1介导IGF-1R信号通路影响ASD认知和社交功能的机制，为开展ASD综合干预提供新的思路。

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders. It has been identified that obesity could aggravate the impairment of cognition and social function in ASD model mouse. Our previous work has reported that methylation levels of SH2B1 were significantly different between identical twins with or without ASD, which implied that SH2B1 gene was correlated to ASD. In the current study, ASD children and BTBR model mice with Sh2b1 knock-out (BTBR+Sh2b1-/-mice) are used as the research objects to analyze the effect of obesity and its major gene SH2B1 on cognitive and social function of ASD. We explore whether SH2B1 mediated Insulin-like growthfactor-1 receptor (IGF-1R) signal pathway to regulate neuronal function impairment and apoptosis, by the neurons derived from human induced pluripotent stem cells (hiPSCs) from ASD patients and BTBR+Sh2b1-/-mice. Furthermore, we also use path clamp technique to detect the effect of SH2B1 mediated IGF-1R signal pathway on voltage-gated potassium channel based on PI3K/Akt/mTOR signal transduction pathways, to explore the potential mechanism whether SH2B1 mediated IGF-1R signal pathway affects cognitive and social function, which could provide new insight contributed to comprehensive intervention of ASD.