视神经脊髓炎（NMO）是亚洲高发的神经系统自身免疫病，致病机理不详，高致残且易复发。目前尚未有明确报道与NMO相关的遗传致病基因。我们前期对多个NMO家系进行全外显子组测序发现存在CNPY3基因突变，提示CNPY3是该病遗传致病因素。我们进一步通过细胞实验证实，CNPY3是TLRs主导的分子伴侣蛋白，其基因突变导致免疫相关的TLRs通路异常。据此我们假设，CNPY3突变通过介导异常TLRs通路，引起机体炎症因子紊乱及Th/Tregs失衡，进而引起血脑屏障破坏与自身抗体产生，最终导致NMO发生或加重。本研究拟通过TLRs通路细胞学模型、患者来源的诱导多能干细胞模型、CNPY3基因突变小鼠模型等探讨CNPY3作为遗传因素导致NMO发病的机制。本研究将首次阐述NMO遗传致病因素，并揭示异常TLRs通路在神经系统自身免疫疾病发生中的重要作用，为精确诊断和靶向治疗奠定基础。

Neuromyelitis optica (NMO) is an autoimmune disease of the central nervous system(CNS), predominantly affecting individuals of Asian origin. The pathogenesis of NMO is not fully understood. Our preliminary study discovered a SNP mutation within the CNPY3 gene co-segregates with NMO in several NMO families by whole-exome sequencing, suggesting a potential pathogenic role of CNPY3 gene. Our further in-vitro study demonstrated that CNPY3 is the predominant chaperone of Toll-like receptors (TLRs), and the mutation results in abnormal TLRs pathway. We hypothesize that CNPY3 mutation is able to cause disorder of inflammatory factors and Th/Tregs imbalance through disturbing the TLRs signal pathway, leading to the damage of blood-brain barrier and the production of autoantibodies，and eventually cause or worsen NMO. The present study intends to investigate how CNPY3 is involved in NMO based on TLRs pathway cell model, patients-derived induced pluripotent stem cell model and CNPY3 transgenic mice model. Our study will demonstrate the mechanism of CNPY3 in the pathogenesis of NMO, and shed light on the important role of TLRs pathway in the autoimmune diseases of CNS.