lncRNA在系统性红斑狼疮患者激素性股骨头坏死中的作用及机制研究

As the primary drug for treatment of SLE, corticosteroids have advantages of rapid suppression of the immune response and inflammation. Howerer, the use of corticosteroids also have many side effects, especially the steroid-induced femoral head necrosis (SFHN), which attracted attention of clinical researchers. More and more studies have found SFHN in SLE patients have a close relationship with SLE disease. It is reported that SFHN rate in SLE patients treated with corticosteroids is about 14.5%. At present, the pathogenesis of SFHN in SLE is not.clear, so it is lacking in early diagnosis and early effective treatment. In recent years, effects of noncoding RNA in bone marrow mesenchymal stem cells drew more and more attention of researchers. This study will screen the differences of lncRNA between SFHN in SLE patients with short-term low does corticosteroids and non-SFHN in SLE patients with long-term large does corticosteroids through chip comparative analysis combined with bioinformatic prediction. Next we will study the effect of the high expression or low expression of lncRNAs on differentiation of bone marrow mesenchymal stem cells using molecular biology technique and further verify its function by animal models. Further the early changes of those lncRNAs in serum of SLE combined with SFHN were researched to explore the early clinical diagnosis value.

糖皮质激素作为治疗SLE的首要药物，具有较快抑制免疫反应和抗炎作用，但使用激素也有不少副作用，尤其是激素性股骨头坏死（SFHN），引起了临床研究人员的重视。越来越多的研究发现，SLE患者发生股骨头坏死与疾病本身关系密切。据报道SLE患者使用激素后SFHN发生率约为14.5%。目前，SLE并SFHN的发病机制尚不清楚，因而缺乏早期诊断的方法，更缺乏有效的、针对性的早期治疗措施。近年来，非编码RNA在骨髓间充质干细胞中的作用受到越来越多的重视。本研究拟通过芯片对比分析，同时运用生物信息学方法筛选短期低剂量使用激素即发生SFHN的SLE患者与长期大剂量使用激素并未发生SFHN的SLE患者间差异性lncRNA，进一步采用分子生物学技术模拟其高表达或低表达对骨髓间质干细胞分化功能的影响并在动物水平进行验证。同时，进一步研究差异性lncRNA在SLE并SFHN血清中的早期诊断学价值。

本研究发现激素型股骨头坏死患者的骨髓间充质干细胞成骨能力下降，并以为切入点，对不同患者的骨髓间充质干细胞进行非编码RNA测序，构建了激素型股骨头坏死非编码RNA表达谱，并通过生信分析，预测了lncRNA-mRNA、lncRNA-miRNA等互作网络。在此基础上，我们发现lncRNA-RP11-154D6可通过与miR-30a的相互作用，影响骨髓间充质干细胞成骨能力，从而在激素型股骨头发生发展中起到重要作用。而另一方面，股骨头坏死患者血液中lncRNA-RP11-154D6表达较对照组明显增加，且与股骨头坏死分期相关，提示我们其可能作为股骨头坏死预测的血液指标。