泛素信号对维甲酸降解通路的调节及其异常在自闭症中的作用研究

自闭症谱系障碍（简称自闭症）系一种病因多样的神经障碍性疾病。本项目合作研究组前期成果表明，维甲酸（RA）合成限速酶ALDH1A2受E3泛素连接酶UBE3A负向调节。过多的UBE3A会破坏RA介导的神经突触可塑性，引起小鼠出现自闭症样表型，补充RA则可缓解症状。这提示维持RA水平对自闭症的治疗可能具有重要意义。.本项目拟通过对RA降解的调控，进一步探究自闭症病理机制和潜在药物靶点。RA的降解由CYP26家族蛋白介导，以后者为切入点，本项目拟开展如下研究：筛选可泛素化修饰CYP26家族蛋白并促使其降解的E3连接酶，在细胞和动物水平上对其进行基因敲除或过表达CYP26蛋白，测定RA水平的变化，检测是否出现自闭症表型。在此基础上，给予CYP26蛋白抑制剂或RA，观察自闭症症状是否改善，从而验证泛素信号调控的RA降解代谢异常在自闭症发生中的重要作用并为自闭症药物研发提供新思路和靶点。

The autism spectrum disorders (ASDs) are a collection of human neurological disorders with heterogeneous etiologies. It has been reported that, the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. Excessive UBE3A dosage could impair RA-mediated neuronal homeostatic synaptic plasticity, whereas RA supplement was shown to alleviate excessive UBE3A dosage-induced ASD-like phenotypes, suggesting that the level of RA has an important role in Treatment of ASD. Therefore, we plan to screen the E3 ubiquitin ligase, which interacts with and ubiquitylates CYP26 protein, the moderator of RA degradation. Furthermore, we will use specific knockout and gene overexpression to confirm the important role of RA in ASDs. This research would hopefully uncover novel target of ASDs drug.