circETS1/miR-1205/FoxP3通过抑制Treg促进SLE活动性的分子机制研究

SLE患者以多个系统器官的炎症为重要临床表现，研究表明，Treg细胞数量减少或功能受损对炎症表现具有重要贡献，然而机制尚不清楚。申请者前期对ETS1在SLE淋巴细胞中的功能进行研究，发现以其为宿主基因的环状RNA早已报道，但功能未知。经背靠背引物和跨剪切位点引物同时qPCR，证实SLE患者PBMC、CD4+ T和Treg细胞中circETS1-006转录水平低于正常对照，CD4+ T细胞中miR-1205显著高于对照；且miR-1205可与FoxP3 3′UTR和circETS1-006结合。本项目拟在此基础上，扩大样本量分析circETS1-006在SLE早期诊断和疾病活动性评价中的应用价值；同时，在细胞和动物模型中深入探讨circETS1-006/miR-1205/FoxP3在Treg增殖、分化、凋亡、分泌及Th17/Treg失衡中的分子机制，为药物治疗靶点开发提供理论和实验依据。

Inflammation involved by multiple systemic and/or organs is main manifestation in patients with SLE. Studies have shown that reduced number or impaired function of regulatory T cells contribute to the inflammation significantly. However, the mechanism is still unclear. In the earlier research, we studied the function of ETS1 in lymphocytes from SLE patients, which was the host gene of circETS1, reported decades years before. Nevertheless, the function of circETS1 was unknown. After qPCR performed by both back-to-back primers and cross-splicing site primers, it was confirmed that relative low expression of circETS1-006 mRNA, not protein, was found in PBMC, CD4+ T and Treg cells from SLE patients by comparing with normal controls. The expression of miR-1205 in CD4+ T cells from SLE patients was significantly higher than that from control. Furthermore, miR-1205 could bind to FoxP3 3 'UTR and circETS1-006 significantly. Based on the discovery, we will expand the sample size to explore the application value of circETS1-006 in early diagnosis and the evaluation of SLE disease activity. At the same time, the molecular mechanisms of circETS1-006/miR-1205/FoxP3 in Treg proliferation, differentiation, apoptosis, secretion and Th17/Treg imbalance will be investigated in cells and animal models to provide theoretical and experimental basis for the development of concise therapy targets.