LncRNA-ston1调控Th17细胞分化参与多发性硬化发病机制研究

Existing immunosuppressive therapy of multiple sclerosis(MS) with broad spectrum and associated side effects limit its efficacy, while the lack of precision regulatory element with high-specificity as therapeutic targets make the development of disease treatment in the bottleneck. In the previous work, the applicant found that the novel regulatory element lncRNA-ston1 involved in the progression of the animal model of MS (EAE) and affects the Th17 cells differentiation, then we proposed that lncRNA-ston1 involved MS pathogenesis by which it affected Th17 cells differentiation though regulating Coro2A expression in the IL-1β signaling pathway. In this project, we will investigate the role of lncRNA-ston1 in the precise regulation of MS/EAE progression and the definite mechanism by which it regulated Th17 cell differentiation, and perfected the biological function annotation of lncRNA. Meanwhile, we evaluated the feasibility of lncRNA-ston1 as MS biomarkers marker and a new therapeutic target. This original work can not only promote the research of lncRNA molecules in the field of MS and autoimmune diseases, but also provide new theoretical guidance for the MS clinical diagnosis and the targeted therapy of precision regulatory elements!

多发性硬化（MS）现有的免疫抑制疗法的广谱性与伴发的副作用限制了其疗效，同时高特异性的精密调节元件治疗靶点的缺乏使得疾病的治疗方法的发展陷入了瓶颈。申请者在前期工作中发现全新的精密调节元件lncRNA-ston1参与MS动物模型(EAE)的病程进展并影响Th17细胞的分化，提出lncRNA-ston1能够通过调节IL-1β信号通路中的Coro2A的表达调控Th17细胞分化进而影响疾病病程进展这一创新性机制设想。本项目将深入探究lncRNA-ston1在MS/EAE病程进展中发挥的精密调控作用及其调控Th17细胞分化的作用机制；完善该lncRNA的生物学功能注释；同时评估该lncRNA分子作为MS生物标志物及全新治疗靶点的可行性。这一原创性工作既能够推动lncRNA分子在MS及自身免疫性疾病领域的研究，也为MS的临床诊断与精密调节元件靶向治疗提供全新的理论指导，促进MS靶向治疗的快速发展！

多发性硬化（MS）是发病机制复杂的神经退行性自身免疫疾病，T细胞亚群失衡在MS发病机制中具有重要作用。该疾病现有的免疫抑制疗法具有广谱性且副作用较大，缺少特异性的治疗靶点。我们通过RNA-seq发现了在MS动物模型（EAE）病程中，部分的lncRNA表达发生了改变。为此我们重点围绕lncRNA分子在MS及EAE中的作用展开工作，在过去的几年中，主要完成了以下内容：1. 证实了lncRNA-ston1参与了EAE病程进展；2. 通过体内和体外试验发现LncRNA-ston1通过与转录因子Stat1结合影响了Th1与Th17的平衡；3. 之前的研究表明lncRNA-NONMMUT031096也参与了EAE的进展，于是我们构建了T细胞特异性NONMMUT031096敲除小鼠。发现在生理状态下，NONMMUT031096表达改变不影响T细胞的分化和发育，在EAE状态下，该分子可以影响EAE的发展；4. 证实T细胞中NONMMUT031096缺失会导致EAE早期外周免疫器官中T细胞亚群失衡，Treg比例升高，Th1和Tc1细胞比例降低；在高峰期减少了中枢神经系统内CD4+ T细胞和CD8+ T细胞的浸润；5. 体外实验表明NONMMUT031096影响了Tc1与Treg的分化。以上结果表明lncRNA分子可通过调节靶基因的表达影响T细胞亚群的平衡，最终参与了EAE的发生发展。这一发现能够推动lncRNA分子在MS及自身免疫性疾病领域的研究，也为MS的临床诊断与靶向治疗提供全新的理论指导，促进MS靶向治疗的快速发展。