原发免疫性血小板减少症中剪接因子SFPQ对T细胞稳态的影响及机制研究

细胞免疫异常在原发免疫性血小板减少症（ITP）的发生发展中至关重要，其中CD4阳性T细胞稳态失衡更是和患者自身抗体产生紧密相关。我们通过分析GEO中ITP患者T细胞表达谱芯片数据发现mRNA剪接因子SFPQ表达降低，ITP缓解后表达回升；也通过实验验证了ITP患者CD4+T细胞中SFPQ表达减少，提示SFPQ和CD4+T细胞稳态异常相关。进一步研究发现SFPQ可以结合mRNA m6A修饰识别蛋白YTHDC1，提示了m6A修饰通过YTHDC1招募SFPQ进行加工剪接的运作模式。本研究拟利用分子生物学、免疫学技术及ITP小鼠动物模型明确SFPQ异常表达对ITP患者T细胞稳态的影响；并结合高通量测序探讨mRNA剪接中SFPQ和m6A修饰的协同作用机制。本项目旨在为ITP的诊断和免疫调节治疗寻找潜在的靶点，并且将为更好地理解mRNA的剪接加工提供理论基础。

Cellular immune abnormalities play crucial roles in the pathogenesis and development of Primary immune thrombocytopenia (ITP). In particular, unbalanced CD4+ T cell homeostasis is important for the production of autoantibody in ITP patient. We analyzed the T cell expression profile of ITP patients from GEO database and found that the expression of mRNA splicing factor SFPQ was decreased in ITP patients, which was recovered after ITP remission. We have also verified the decreased expression of SFPQ in CD4+T cells in ITP patients, suggesting that SFPQ may be related to the dysfunction of CD4+T cells. Further mechanistic study found that SFPQ could bind to YTHDC1, which is a reader protein of m6A modification, suggesting that m6A modification might recruit SFPQ through YTHDC1. This project intends to use molecular biology techniques, immunology techniques and ITP mouse model to elucidate the effect of SFPQ abnormal expression on T cell homeostasis in ITP patients, and explore the synergistic mechanism of SFPQ and mRNA m6A modification in mRNA splicing by high-throughput sequencing. Our project aims to find potential targets for the diagnosis and immune-modulatory therapy of ITP, and will provide theoretical basis for a better understanding of mRNA splicing.