MicroRNA-124对帕金森病中多巴胺能神经元的保护作用及机制研究

Parkinson's disease (PD) is a kind of degenerative disease of the central nervous system seen more commonly in olders. Research works showed that the neural inflammation mediated by microglial cells play an important role in PD's pathological progress. However, the method intervening microglial activation to slow the process of PD has not been established. MicroRNA(miR)-124 plays a crucial role in sustaining the microglia quiescence as well as suppressing the central inflammation. Our previous study showed that miR-124 can protect dopaminergic neurons though inhibiting the activity of microglial cells in PD animal models, and this protective effect might be associated with the caspase signaling. On this basis, this project tries to verify the effects of miR-124, including suppressing the microglial activation and its release of inflammation factors and preventing and improving PD symptoms by reducing the toxic effects on dopaminergic neurons, are involved in the activation of caspase signaling pathway in molecular, cellular and animal model levels; simultaneously, we will also perform the correlation analysis between miR-124 and the onset, grade and drug efficacy of PD in clinical level. Our study might clarify the role and machanisms of miR-124-mediated microglial regulation in the progression of PD, therefore contribute to the present knowledge of PD's molecular biology, provide new target for biological intervention of PD, and explore quantitative index of the clinical diagnosis and the therapeutic evaluation of PD.

帕金森病（PD）是中老年常见的神经退行性疾病，研究表明小胶质细胞活化及其介导的神经炎症在PD进展中发挥重要作用，但干预小胶质细胞活化延缓PD进程的有效方法尚未建立。MicroRNA(miR)-124在小胶质细胞静息态维持和抑制中枢炎性反应起关键作用。我们前期在PD模型中发现miR-124可抑制小胶质细胞活性保护多巴胺(DA)能神经元，且该保护作用与caspase信号通路有关。本课题拟在此基础上，从分子、细胞、动物模型水平验证miR-124是通过对caspase信号通路的调控作用抑制小胶质细胞活化及炎症因子释放，进而降低对DA神经元毒性作用，预防和改善PD症状；同时在临床水平对miR-124与PD发病、分级和药物疗效进行相关性分析。该研究不仅可以丰富现有对PD分子生物学机制的认识，为PD药物治疗提供新的靶点，也有望发掘PD临床诊断和疗效评价的量化指标。

帕金森病（PD）是中老年常见的神经退行性疾病，其发病机制仍不十分明确。研究表明小胶质细胞介导的中枢炎症是帕金森病的重要发病机制，因此明确小胶质细胞的活化机制对深入研究PD发病机制有重要意义。miRNA是小胶质细胞活化的重要调控因素，已有研究表明miR-124是调控小胶质细胞活化的重要因子。基于此，本课题拟从分子、细胞、动物模型、临床四个水平逐层深入阐述miR-124通过抑制小胶质细胞活性，从而对PD中DA神经元产生保护作用。我们通过一系列体内外实验证明miR-124一方面可通过靶向抑制p38-α，抑制小胶质细胞的活化；另一方面也可通过靶向抑制MEKK3/NF-κB通路，抑制小胶质细胞的活化，简接保护多巴胺神经元；不仅如此，miR-124还可通过靶向抑制BIM及AMPK/mTOR 通路直接调控多巴胺神经元的自噬及凋亡水平。