LASP1 SUMO/DeSUMO修饰在焦虑调控中的作用和机制

近半个世纪的抗焦虑药治疗几乎没有新的突破，且这些抗焦虑药物还存在药效缓慢、效果不彻底和严重副作用等问题。究其原因是因为焦虑症的具体发病机制尚不清楚。本项目前期结果表明：前脑或杏仁核脑区SENP3缺失均可导致小鼠表现为高焦虑，且突触后膜AMPARs表达增加；SENP3 cKO小鼠LASP1处于高度SUMO修饰状态； LASP1 SUMO修饰调控LASP1与Arc的结合。据此，本项目将围绕LASP1 SUMO/DeSUMO修饰在焦虑调控中的作用和机制开展研究，主要研究内容包括：确定LASP1 SUMO修饰参与焦虑的调节； LASP1 SUMO修饰与磷酸化的关系及功能；确定LASP1 SUMO修饰对其互作蛋白的调节及参与焦虑调控的分子机制。为进一步理解焦虑症的发病机制提供新的观点，也将有助于对焦虑症新药物靶点的发现提供线索。

In the past half-century, there have been almost no breakthroughs in the treatment of anti-anxiety drugs, and these anti-anxiety drugs still have many problems such as slow efficacy, incomplete effects, and serious side effects. The reason is that the specific pathogenesis of anxiety disorders is still unclear. Our preliminary results show that the deficiency of SENP3 in the forebrain or amygdala can cause high anxiety, and increased expression of AMPARs in the postsynaptic membrane; The SUMOylation of LASP1 is increased in SENP3 cKO mice; LASP1 SUMOylation could regulate the binding between LASP1 and Arc. Our project will focus on the role and mechanism of LASP1 SUMOylation in the regulation of anxiety. The main research content includes: Define that LASP1 SUMOylation participates in the regulation of anxiety; Define the relationship between LASP1 SUMOylation and its phosphorylation; Define the regulation of LASP1 SUMOylation on its interaction protein and the molecular mechanism involved in anxiety regulation. It will provide new insights for further understanding of the pathogenesis of anxiety disorders, and will also help provide clues to the discovery of new drug targets for anxiety disorders.