肌萎缩侧索硬化症（ALS，俗称“渐冻人”症）是一种由于大脑皮质、脑干和脊髓前角的上下运动神经元受损而导致的神经致死性疾病。ALS 的病理机制极为复杂，目前尚无药物可治愈ALS。最新Nature报道C9orf72基因非密码区六核苷重复扩增序列(GGGGCC)n可形成G-四链体结构，该结构影响ALS病程，为ALS的致病机制和治疗提供了新的思路。该课题拟设计合成出具有稳定或解旋G-四链体功能的一系列配体及配合物，通过化合物结构设计实现对C9orf72基因六核苷重复扩增序列G-4 DNA和RNA的选择性识别，并研究配体和配合物对RNA转录，无ATG相关翻译，RNA foci和核蛋白的影响，评价化合物对ALS患者细胞的影响作用机制,并在分子及细胞水平上探讨ALS病理机制，并揭示其构效关系。此研究可为明确ALS致病机制，同时为小分子药物对ALS的基因疗法提供理论和实验基础。

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which is resulted from loss of motor neurons in the motor cortex, brain stem, and spinal cord. The pathogenesis of ALS disease is very complex, and currently there is no cure or effective preventative treatment for ALS. However, with the discovery that a GGGGCC repeat expansion in C9orf72 is structural polymorphism which can form G-quadruplex, a new therapeutic approach for ALS has come to light. Capitalizing on the above findings, we will rationally design small molecules (ligands and complexes) which are able to selectively stabilize or unfold G-quadruplex through structural changes. Furthermore, the effect of RNA transcripts, repeat-associated non-ATG (RAN) translation, RNA foci formation in cultured cells expressing (GGGGCC)n and cell biological behaviors induced by compounds will be studied too. The pathogenesis of ALS and structure—activity relationship will be discussed at the molecular and cellular levels. These studies will gain valuable insight into the pathogenesis of ALS, and provide theoretical and experimental basis for exploring new drugs as well as gene therapy for ALS.