LncRNA n335494调控异位生发中心形成在舍格伦综合征中的作用研究

Sjogren’s syndrome(SS) is an autoimmune disease. The lesion usually focused on salivary gland. The clinical feature of the disease is characterized by severe dry mouth, dry eyes and parotid swelling. The pathogenesis is unclear. A small part of patients are likely to have lymphoma. Ectopic germinal center(EGC) found in salivary gland usually associated with higher disease activity and canceration rate. Studies proved that lymphotoxin(LT) play an important role in the formation of EGC. Our previous study revealed that lncRNA n335494 was up-regulated in labial salivary gland of SS patients, especially in patients with EGC. The expression level of n335494 was positively correlated with disease activity. Further studies demonstrated that n335494 could regulate the expression of LT by cis regulation mechanism and involved in the formation of EGC. Concluded, the study will reveal the mechanism of lncRNA n335494 regulated the expression of target gene LT and the role of n335494 in the formation of EGC in SS. The study aims at strong scientific evidence for improving the disease diagnosis and drug therapy.

舍格伦综合征（SS）是一种自身免疫性疾病，常累及以唾液腺为主的外分泌腺，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，部分可恶变为淋巴瘤。SS靶器官唾液腺组织中异位生发中心（EGC）的出现与疾病的高活动性及高恶变率密切相关，已有研究证实淋巴毒素（LT）与EGC形成密切相关。课题组前期研究发现lncRNA n335494在SS患者唾液腺组织中显著升高并与疾病活动性呈正相关，且在出现EGC的患者中升高更加明显。进一步预初实验发现n335494可能通过cis调控方式调控LT的表达水平而在EGC的形成中起一定作用。因此，本项目拟通过实验进一步明确n335494调控靶基因LT的分子机制，初步揭示其在SS靶器官中EGC形成过程中的作用机制，以期为寻找新的更具特异性的药物治疗靶点提供研究基础。

舍格伦综合征(Sjogren's syndrome, SS)是一种自身免疫性疾病，早期由细胞免疫诱导，而随着疾病进展，则导致体液免疫系统亢进并攻击唾液腺等外分泌腺造成器官功能性破坏。本研究从SS细胞免疫和长链非编码RNA(Long non-coding RNA, LncRNA)入手，挖掘了相关免疫异常及潜在的分子机制。首先，我们在前期基础上探讨了LncRNA PVT1的异常激活对细胞免疫的影响，发现LncRNA PVT1在CD4+T细胞中通过Myc调控糖酵解水平，进而影响免疫细胞增殖以及效应分化。另外，我们在本项目的平行研究中通过药物虚拟筛选结合生物试验验证，发现药物青蒿琥酯和防己诺林碱在SS体液免疫调节中具备一定疗效，并对青蒿琥酯进行了分子机制挖掘，发现青蒿琥酯通过影响TRAF6的泛素降解调节下游NFκB活性进而调控B淋巴细胞的存活及SS异常体液免疫应答。本研究从SS的细胞免疫、体液免疫调控两方面着手，部分揭示LncRNA PVT1和青蒿琥酯的在SS中的免疫调控机制，为SS的发病机制和药物治疗提供理论依据和实践基础。