利用单细胞测序技术研究PRMT5在多发性硬化和克罗恩病中的不同作用及其机制研究

II型精氨酸甲基转移酶PRMT5能单甲基化或对称性二甲基化蛋白精氨酸残基，参与mRNA剪切,蛋白修饰,信号转导等，已发现在肿瘤中起重要作用，但在自身免疫病中作用鲜有报道。我们前期研究发现CD4-cre-PRMT5fl/fl条件敲除鼠外周T细胞数量降低，小鼠造模实验性脑脊髓膜炎EAE不发病，但在TNBS诱导实验性小鼠肠炎模型中发病严重。T细胞特异性敲除PRMT5为什么在多发性硬化和克罗恩病两种以CD4+T细胞主要介导的自身免疫模型中出现截然不同作用？我们拟通过CD4-cre-PRMT5fl/fl条件敲除鼠造模，利用单细胞RNA-seq，检测两种模型下细胞亚群数量功能变化，找到影响疾病结局的关键致病或调节细胞亚群；利用单细胞ATAC-seq，明确条件敲除鼠分别在两种疾病模型下调控T细胞及其它关键细胞亚群分化的重要核转录因子，为阐明多发性硬化和克罗恩病发病机制及治疗提供新的理论和靶标。

PRMT5 is the type II arginine methyltransferase, and capable of monomethylating or symmetrically dimethylating protein arginine residues and is involved in mRNA splicing, protein modification, signal transduction, etc., and has been found to play an important role in many tumors. However, its role in autoimmune diseases is rarely understood. Our previous study found that the number of peripheral T cells in CD4-cre-PRMT5fl / fl conditional knockout mice was reduced, resitanced to EAE mouse model, but severely in the experimental mouse enteritis model induced by TNBS. Why T cell-specific knockout of PRMT5 appear to be distinct in multiple sclerosis and Crohn's disease, the two autoimmune disease models primarily mediated by CD4 T cells? We plan to use CD4-cre-PRMT5fl / fl conditional knockout mice and use single-cell RNA-seq to detect changes in the number and function of cell subpopulations under these two diseases, to find the key pathogenic or regulatory cell subpopulations that affect disease outcomes. Also using single cell ATAC-seq to find the important factors that regulate T cell and other key cell subpopulations diffenentiation in the two mouse models, provides theoretical basis and targets for elucidating the pathogenesis and treatment of multiple sclerosis and Crohn's disease.