光敏相关性microRNA筛查及其在紫外线诱发狼疮中的作用机制研究

Ultraviolet(UV) impact on human health, cause skin photosensitivity reactions, which is an important environmental factors induced lupus, the mechanism of UV photosensitization and its induced lupus is still unknown. Our previous study found that: microRNAs play a role in the regulation of DNA methylation, P53, sp1, expressions of DNMT1 and other factors to promote expression of CD11a/CD18, CD70 costimulatory molecules to induce lupus; lupus patients photosensitivity reactions can be induced by ultraviolet that can affect the regulation of DNA methylation, DNMT1 espression. The research group's latest study confirmed the presence of photosensitve-related microRNA，and may be involved in the pathogenesis of lupus. Therefore, this study intends to adopt high-throughput technologies such as gene chips screened photosensitve-related microRNA luciferase reporter gene system, low expression, over-expression of a specific microRNA, in vitro and in vivo intervention to research, explore its target genes the role of molecular regulation in many ways. The results will clarify UV photosensitive mechanism and its role in gene activation pathway of lupus induced by UV; provide effective new target for photosensitivity disease and lupus treatment, that has important theoretical and clinical significance.

紫外线影响着人类健康，引起皮肤光敏反应，是诱发狼疮的重要环境因素，目前紫外线的光敏作用及其诱发狼疮的机制不明。我们的前期研究发现：microRNA通过对DNA甲基化、P53、sp1、DNMT1等因素的调控作用，促进CD11a/CD18、CD70等共刺激分子的表达进而诱发狼疮；紫外线可诱发狼疮患者的光敏反应并影响DNA甲基化、DNMT1 等调控因素。课题组的最新研究证实存在光敏相关性microRNA，并可能参与诱发红斑狼疮。因此本研究拟采用基因芯片等高通量技术筛选出光敏相关性microRNA，再通过荧光素酶报告基因系统、低表达、过表达特定microRNA、体内外干预等多途径研究，探讨其对靶基因的分子调控作用。研究结果可阐明紫外线的光敏机制及其在诱发狼疮基因活化通路中的作用；可为光敏性疾病和狼疮的治疗提供有效新靶点，具有重要理论和临床意义。

紫外线是人类健康的重要影响因素之一，临床上主要引起皮肤光敏反应，是诱发狼疮的重要环境因素，本项目通过一系列的研究探讨了紫外线诱发狼疮的机制。本研究采用基因芯片等高通量技术筛选出光敏相关性microRNA：miR-29b、miR-17、miR-630、miR-155、miR-671-5p、miR-222，再通过荧光素酶报告基因系统、低表达、过表达特定的microRNA、体内外干预等多途径研究，探讨光敏相关性microRNA对靶基因的分子调控作用。研究发现：光敏相关性microRNA可以下调DNA 甲基化和CD11a、CD70 基因启动子区甲基化水平、sp1 和DNMT1 的表达；而microRNA inhibitor可以上调DNA 甲基化和CD11a、CD70 基因启动子区甲基化水平、sp1 和DNMT1 的表达，从而下调SLE 患者CD11a 和CD70 基因mRNA 水平和蛋白水平；MRL/lpr狼疮易感小鼠体内干预实验显示microRNA干预组的狼疮易感小鼠尿蛋白浓度具有上升趋势、肾脏病理组织中可见大量的淋巴细胞浸润。本研究结果初步阐明了紫外线的光敏机制及其在诱发狼疮基因活化通路中的作用，可为光敏性疾病和狼疮的治疗提供新的靶点，具有重要理论和临床意义，同时有助于今后开展转化医学。