原发性舍格伦综合征中TLR9异常高表达的分子调控及发病机制研究

Primary Sjogren’s syndrome(pSS) is an autoimmune disease which is characterized by severe dry mouth, dry eyes and parotid swelling. The pathogenesis of pSS is unclear. Toll like receptor 9(TLR9) is a kind of pattern recognition receptors, which induce the activation of innate immunity, and activating adaptive immunity. Our research focused on the role of TLR9 in the pathogenesis of pSS. The expression level of TLR9 was observed significantly up-regulated in salivary gland epithelial cells of pSS. The TLR9 signal pathway was activated at the early stage of the disease. Early application of TLR9 inhibitor can effectively prevent the process of pSS in the animal models of the disease. It is indicated that TLR9 might play an important role in the pathogenesis of pSS. Based on our previous research, this project aimed to explore the mechanism of the dysregulated TLR9 in sailvary gland epithelial cells of pSS. By conducting the functional experiments, the study will reveal the mechanism of LncRNA n340599 regulate the expression level of TLR9. By using the clinical samples and pSS mouse models, the study will reveal the mechanism of TLR9 induced type I IFN signal pathway in the progression of pSS and the regulation mechanism of the upregulated LncRNA n340599 in salivary gland epithelial cells. By conducting the systemic up- and down-stream researches, our project will reveal the molecular mechanism of dysregulated TLR9 in pSS and provide strong scientific evidence for improving the disease diagnosis and drug therapy.

原发性舍格伦综合征（pSS）是一种自身免疫性疾病，常累及外分泌腺，临床表现为严重的口干、眼干以及腮腺区反复肿胀，病因尚不明确。Toll样受体9（TLR9）是一种模式识别受体，可诱发固有免疫激活进而激活适应性免疫。申请人前期研究表明TLR9在pSS患者腺上皮细胞中表达显著增高并在发病早期显著激活，同时应用TLR9抑制剂可有效阻止模型鼠的疾病进程，提示TLR9可能在pSS发病中起重要作用。本项目拟在前期研究基础上，探究pSS唾液腺上皮细胞中TLR9异常高表达的分子调控及发病机制，揭示LncRNA n340599在腺上皮细胞中调控TLR9异常高表达机制。进一步利用临床样本资源结合模型鼠干预性实验，明确TLR9下游I型干扰素信号通路活化诱导pSS发病的分子机制。通过本课题从上下游系统性研究有望获得异常高表达TLR9 在pSS 发病中的作用及机制，进而为临床诊断和寻找新的药物治疗靶点提供科学依据。

舍格伦综合征（Sjogren's syndrome, SS）是由免疫系统异常攻击唾液腺导致的自身免疫性疾病，本研究从先天性免疫信号和长链非编码RNA（Long non-coding RNA, LncRNA）两个角度，挖掘了相关免疫信号异常激活导致的影响及潜在的分子机制。首先，我们在前期基础上探讨了先天性免疫信号Toll样受体9（Toll-like receptor 9,TLR9）的异常激活对唾液腺上皮细胞的影响，发现TLR9激活介导下游的p38/MAPK和JNK信号通路，并以此调控细胞的自噬和凋亡水平。另外，我们通过芯片筛选获取了SS病变唾液腺差异表达的LncRNA，发现LncRNA PVT1在SS患者的CD4+T细胞中显著高表达，并明确其能响应T细胞先天性免疫信号通路，通过转录因子Myc调控了CD4+T细胞的糖酵解水平，参与细胞的增殖和Th1向效应分化。进一步通过体内模型观察和抑制剂处理，我们明确SS发生时存在异常的糖酵解，并初步确认上述改变能调控CD4+T细胞浸润，参与SS发病进程。本研究部分揭示了先天性免疫信号通路在唾液腺细胞、免疫细胞代谢和自身稳态中的调控网络，为SS的发病机制和靶向治疗提供理论依据和实践基础。