睡眠障碍诱发的类固醇激素节律异常在SLE中的作用及狼疮定的干预研究

Sleep problems have become a prominent issue in the world. Epidemiological studies have found that sleep disorders may increase the risk of autoimmune diseases such as systemic lupus erythematosus (SLE). Steroid hormone plays an important role in the development of SLE. The secretion rhythm of hormone is regulated by the biological clock system. So, we speculate that abnormal hormone rhythm caused by sleep disorder may promote the occurrence of SLE. Most of the hormones are extremely in low concentration and there is a complex metabolic network among steroids. We have developed a holistic method for the analysis of steroid hormones, which enables highly sensitive detection of more than 40 hormones and their metabolites. The influence of sleep disorder on steroid rhythm and biosynthesis related enzymes are measured based on the sleep deprivation (SD) model; then, the effect of SD on lupus disease activity is evaluated by the inflammatary cytokines. The relationship between hormone rhythm abnormalities and the occurrence and development of SLE is elucidated using correlation analysis. Futher, it is explored whether Langchuangding can improve the hormone secretion through regulating the expression of clock genes. The study will reveal the relationship between the disturbance of the biological clock and autoimmune diseases, and provide a theoretical basis for the treatment of SLE by traditional Chinese medicine.

现代社会睡眠问题越来越突出，流行病学研究发现睡眠障碍增加了系统性红斑狼疮（SLE）等自身免疫疾病的风险。类固醇激素在SLE发生发展中有重要作用，其分泌节律受生物钟系统调控，因而我们推测睡眠障碍引起的激素节律异常可能会促进SLE发生。体内激素大部分浓度极低，且存在复杂的代谢网络，申请人特别开发了类固醇激素的全景分析方法，可以对40多种激素及其代谢物水平进行高灵敏检测，通过对睡眠剥夺（SD）模型类固醇激素及合成关键酶的分析，系统地阐明SD对激素分泌节律的影响；进一步考察SD对狼疮病情的影响，明确激素节律异常与SLE发生发展中的相关性；并探讨中药狼疮定是否通过调节钟基因的表达来改善激素分泌从而治疗SLE。本研究将进一步揭示生物钟紊乱与自身免疫疾病间的关系，同时为中医药治疗SLE提供理论依据。

现代社会睡眠问题越来越突出，流行病学研究发现睡眠障碍增加了系统性红斑狼疮(SLE)等自身免疫性疾病的风险，但其机制仍未阐明。睡眠障碍是生物节律失衡的常见原因之一，生物节律失衡会影响机体代谢网络，从而促进多种疾病的发生。本项目主要研究结果如下：(1)利用自发狼疮转基因MRL/lpr小鼠建立SLE疾病的睡眠剥夺模型，根据生活中常见的睡眠障碍类型构建了急性睡眠剥夺和慢性睡眠剥夺两种模型，通过对小鼠脑电波与肌电波、行为学的监测，证实睡眠剥夺能够破坏MRL/lpr小鼠睡眠节律，降低小鼠自主行为及记忆能力。(2)慢性睡眠剥夺会加剧MRL/lpr小鼠生物节律失衡和病情恶化，相关性分析表明生物节律失衡可能与SLE病情严重程度有关。(3)完善了高灵敏的类固醇激素代谢轮廓分析方法，实现对小鼠尿液中43种类固醇化合物的全景分析，描绘了睡眠剥夺MRL/lpr小鼠类固醇激素的特征代谢谱，发现睡眠剥夺会干扰类固醇激素代谢过程，尤其是急性睡眠剥夺会导致雄性激素、雌性激素、孕激素、甾醇均出现不同程度变化。(4)生物节律失衡不仅影响激素代谢，对其他代谢过程也有重要的调节作用，采用非靶向代谢组学研究发现慢性睡眠剥夺诱导的生物节律失衡可能通过引起多条氨基酸代谢通路紊乱来加快SLE疾病进展。(5)中药狼疮定能调整MRL/lpr小鼠生物节律，并且改善类固醇激素代谢和氨基酸代谢异常，有助于缓解睡眠剥夺引起的SLE病情恶化。以上结果能为揭示生物节律紊乱与自身免疫性疾病间的关系提供新的证据，为中药治疗SLE提供一定的理论依据。