靶向泛素连接酶UBE3A过表达相关人类自闭症的模型建立、机制研究及化学干预

自闭症谱系障碍，简称“自闭症”，又名“孤独症”，是一种严重的神经发育障碍性疾病。在前面研究工作中，我们已经阐明了泛素连接酶UBE3A过度激活与自闭症表型间存在相互关联的分子机制，ALDH1A家族蛋白泛素化修饰对于UBE3A过表达所引起的自闭症发生过程具有重要的作用，从而为自闭症临床诊断和治疗提供关键的分子靶点。我们期望通过计算机模拟筛选，针对UBE3A自身T508位点的磷酸化修饰，以及UBE3A-ALDH1A家族蛋白间的互作区域进行小分子化合物的化学干扰，从而实现化学干预过度活化的UBE3A连接酶活性，抑或阻断结合UBE3A下游重要的底物蛋白来为自闭症这一重大疾病，特别是母本染色体15q11-q13扩增等UBE3A功能过度激活相关的自闭症亚型，提供有效的治疗手段。

The autism spectrum disorders (ASD) are a collection of human neurological disorders with heterogeneous etiologies. In our previous studies, we have found the reduced RA signaling as an underlying mechanism in ASD phenotypes linked to UBE3A hyperactivities, also provided the therapeutic targets against increasingly occurring ASD. By virtual screening, we plan to target the UBE3A T508 phosphorylation site with hyperactive E3 ligase activity, and the interaction between UBE3A-ALDH1A family proteins using chemical intervening strategies. Further, the candidate compounds could be attempted to inhibit the hyperactive UBE3A, or block its interactions with important downstream substrates, therefore provides an effective treatment for ASD, especially the subtype associated with UBE3A , such as maternal chromosome 15q11-q13 amplification.