抑郁症miR-34b/c调控紊乱及临床转化研究

Depression is a common and harmful mental disease. It is urgent to explore the physiopathological mechanism and the biomarkers for diagnosis and treatment of depression. Until recently, more attention are paid on the hypothesis of microRNA dysregulation. Our preliminary study indicated that miR-34b and miR-34c expression levels in the peripheral blood leukocytes were higher in depression, and miR-34b/c gene polymorphisms were the susceptibility factors for depression and cognitive function. Previous work showed that miRNAs play a critical role in the pathogenesis and anti-depressive treatment. In view of this, we speculate that dysregulation of miR-34b/c may impact the occurrence and development of depression. In this study, by utilizing the technology of molecular genetics, neurobiology and neuropsychology and so on, we will compare not only the mRNA, the protein expression of miR-34b/c and target genes, but also the subtype, clinical symptoms, antidepressant efficacy and cognitive function, in the depression animal models, as well as in patients with depression. Strive to answer: (1) Is the dysregulation of miR-34b/c related to the pathogenesis of depression and neural plastic function? (2)The clinical value of miR-34b/c in peripheral blood on the early diagnosis and individualized treatment of depression. These findings can promote the understanding the miRNA epigenetic regulation mechanism in depression, and provide new theoretical and experimental basis for the prevention of depression.

抑郁症是一种危害性极大的精神疾病，探明其病理机制，找到可能影响其发生及转归的生物学标记物意义重大。近年来microRNA调控紊乱备受关注。课题组前期研究提示抑郁症存在外周血miR-34b、miR-34c表达异常，miR-34b/c基因多态性与抑郁症发病及认知功能相关。结合既往miRNA调控异常影响抑郁症的研究进展，我们推测：miR-34b/c调控紊乱可能影响抑郁症发生发展。本项目将整合动物和人群实验研究，综合利用分子遗传、神经生物、神经心理等技术，通过比较miR-34b/c和靶基因mRNA/蛋白表达与抑郁亚型、临床症状、疗效以及认知功能等指标差异，力争回答:(1) miR-34b/c调控紊乱是否影响抑郁症及神经可塑性功能；(2) miR-34b/c调控紊乱在抑郁症诊断和个体化治疗的临床意义。其结果可为进一步明确抑郁症的miRNA表观遗传调控机制，为抑郁症的防治提供新的理论和实验依据。

抑郁症是一种危害性极大的精神疾病，探明其病理机制，找到可能影响其发生及转归的生 物学标记物意义重大。近年来microRNA调控紊乱备受关注，课题组基于前期研究发现，综合利用分子遗传、神经心理、神经影像等技术，比较miR-34b/c表达和基因多态性与抑郁亚型、临床症状、疗效、认知功能的关系，并分析了神经影像指标与抑郁症临床症状和转归的关联性。结果发现：1）miR-34家族研究：抑郁症外周血中存在miR-34a-5p、miR-34c-5p表达升高，抗抑郁治疗后明显降低，其表达水平与抑郁症严重程度呈正相关，但ROC 曲线分析显示其敏感性和特异性仍显不足。MiR-34b/c基因多态性与抑郁症发病相关，同时也与抑郁症患者工作记忆、延迟记忆、言语功能、P300主成分潜伏期等认知功能相关联。生物信息学分析miR-34家族在细胞凋亡、神经可塑性以及细胞免疫等相关信号通路中也发挥着重要调控作用。2）神经影像学研究：抑郁症胃肠道症状患者组在左侧额中回、中央前回、右侧额上回、额中回的GMV和ReHo明显降低。难治性抑郁组在右侧感觉/躯体运动区、右侧听觉和左侧默认模式网络区ALFF明显增高。临床痊愈抑郁症患者仍存在异常连接的脑区，包括：右侧楔前叶、左侧额上回、右侧舌回。其结果将为抑郁症的诊疗提供新途径和新方法，为进一步深入研究抑郁症的病理机制、诊疗试剂盒或标准的开发提供新视角，最终达到个体化治疗的目的。