系统解析MicroRNA 127-3p 在狼疮肾炎发生病理过程中的调控机理

Lupus nephritis, whose mechanism has been intensively studied by scientists, is a common complication of Systemic Lupus Erythematosus(SLE) and a major cause of death among people with SLE. So far, besides the abnormal immune responses in SLE, renal cells are considered to play an important role in the process of kidney inflammation and damage. Overreacted type I interferon response in renal cells was found essential for the development of lupus nephritis; however, its mechanism is still not clear. MicroRNAs (miRNAs) are key factors in regulating gene expression and are extensively involved in the immune dysregulation of SLE. In our pilot study of the expression profile of miRNAs in the kidneys from lupus nephritis patients, we found that hsa-miR-127-3p was expressed lower than that in the kidneys from healthy people. We further investigated its function and found that hsa-miR-127-3p could negatively regulate the signal transduction of type I interferon. Based on these results, we propose the following project: 1. Studying the mechanism for hsa-miR-127-3p in regulating type I interferon signal transduction which includes identifying the targets of hsa-miR-127-3p that are responsible for its regulatory function; using western blot to detect the changes in signaling events; doing gene array experiments to identify the genes regulated by hsa-miR-127-3p. 2. Studying how the transcription of hsa-miR-127-3p is regulated in renal cells and why hsa-miR-127-3p is expressed abnormally in lupus nephritis. 3. Exploring the possibility of treating lupus nephritis by hsa-miR-127-3p. By conducting the above studies, we will learn more deeply about the pathogenesis of lupus nephritis and our results will provide a new therapeutic target for the treatment of lupus nephritis.

狼疮肾炎是系统性红斑狼疮的主要合并症和死亡原因，其发病机制已成为狼疮研究的热点。除免疫紊乱外，肾脏细胞在其炎症损伤中的作用也非常重要，肾脏I型干扰素通路的过度活化是狼疮肾炎发病的必要条件，但其机制仍不清楚。miRNA是基因表达调控的关键分子，在狼疮的免疫紊乱中有重要作用。在检测狼疮肾炎的肾脏miRNA表达中，我们发现hsa-miR-127-3p的表达异常降低。进一步，我们发现hsa-miR-127-3p能抑制I型干扰素信号的传递。在此基础上，本课题拟对hsa-miR-127-3p的靶基因进行鉴定，并利用western blot，基因芯片等技术对hsa-miR-127-3p调节I型干扰素通路的机制进行研究；对肾脏hsa-miR-127-3p的转录调控及表达异常的机制进行研究；探索用hsa-miR-127-3p治疗狼疮肾炎的可行性，为阐明狼疮肾炎的发病机理、寻找新治疗靶点提供理论和实验依据。

狼疮肾炎是系统性红斑狼疮的主要合并症和死亡原因，其发病机制已成为狼疮研究的热点。除免疫紊乱外，肾脏细胞在其炎症损伤中的作用也非常重要，肾脏I型干扰素通路的过度活化是狼疮肾炎发病的必要条件，但其机制仍不清楚。miRNA在狼疮的免疫紊乱中有重要作用。我们在狼疮肾炎的肾脏miRNA表达谱中，发现hsa-miR-127-3p的表达异常降低。进一步，我们证明了肾脏系膜细胞内源表达的hsa-miR-127-3p能抑制I型干扰素信号的传递，而hsa-miR-127-3p的这种抑制功能是通过靶向I型干扰素通路的关键信号传导分子JAK1并抑制其表达而实现的。同时，我们证明了狼疮肾炎患者体内持续的I型干扰素通路的活化可以抑制肾脏hsa-miR-127-3p的表达。于是，我们的研究结果提示了，在狼疮肾炎发病过程中，存在着一个由I型干扰素通路的长期活化而导致的该通路的正反馈增强环路，通过过表达hsa-miR-127-3p将可能扭转异常的通路过度活化过程，缓解狼疮肾炎的发病。最后，我们利用hsa-miR-127-3p类似物探索了体内过表达miR-127-3p抑制I型干扰素通路的可行性。与此同时，作为课题的延伸，我们发现I型干扰素可以诱导肾脏系膜细胞中hsa-miR-744的表达，而hsa-miR-744的高表达可以抑制负调节分子PTP1B的表达，从而促进肾脏系膜细胞中I型干扰素非经典信号通路的活化，促进CCL2、CCL5、IL6等炎症基因的表达。另外，我们还发现miR-130b可以通过靶向IRF1抑制IFN通路激活。我们的研究进一步阐明了miRNA参与I型干扰素通路的调控以及狼疮肾炎的发病的过程的机制，为寻找新治疗靶点提供了理论和实验依据。