miR-144/451调控帕金森病发生发展的作用及机制

Parkinson’s disease (PD) is the second most common neurodegenerative disease, yet its etiology and pathogenesis are poorly understood. The microRNAs, as an epigenetics mechanism, seem to play an important role in the pathogenesis of Parkinson’s disease. Our previous study showed that the miR-144/451 can effectively antioxidant responses by repressing 14-3-3zeta. Our previous study showed that the dopaminergic neuron lesion in substantial nigra of the miR-144/451-/- PD mice is more worse than that of wide type mice. It revealed that there is close relationship between miR-144/451 and the fate of dopaminergic neurons in PD. Therefore, in the present study, it is planned to investigate the role of miR-144/451 during PD using the miR-144/451-/-mice and the in vivo and vitro PD model from different levels. Further more, we will detect the change of some important up and down stream factors in the Akt/14-3-3/FOXO pathway following the miR-144/451 treatment. The purpose of this study is to explore the role and mechanism of the miR-144/451 in the fate of dopaminergic neurons in PD, and open up a new direction or concept for PD therapy and provide reliable theoretical basis for it.

帕金森病是目前第二大神经退行性疾病，发病机制尚未清晰。非编码RNA作为表观遗传机制在帕金森病的发生发展过程起着重要作用。项目申请人课题组的前期研究结果表明，miR-144/451具有极强的抗氧化特性；预实验结果显示，敲除miR-144/451加重了帕金森病小鼠黑质-纹状体系统的损伤，提示其与帕金森病中多巴胺能神经元的命运关系密切，但miR-144/451调控的方式和机制未被阐明。本课题拟应用miR-144/451敲除鼠，研究miR-144/451对帕金森病中的调控作用；检测多巴胺神经元中Akt/14-3-3/FOXO信号通路上下游主要因子的表达，阐明Akt/14-3-3/FOXO通路与miR-144/451之间的对话关系，筛选关键性作用因子。本课题旨在通过研究miR-144/451调控帕金森病发病过程的作用及机制，以期为帕金森病及其它神经退行性疾病寻找新的治疗方向，提供切实可靠的理论依据。

miR144/451 参与了帕金森病中多巴胺能神经元的变性和死亡的过程。本课题利用miR144/451双敲除小鼠，通过腹腔注射MPTP、脑内注射6-OHDA建立PD小鼠模型；并将A53T转基因PD小鼠和miR144/451双敲除小鼠杂交等方法观察miR144/451在帕金森病发生发展中发挥的作用。同时，本课题利用MPP+孵育SH-SY5Y细胞制作PD模型，并制作miR144/451过表达和敲除的质粒转染入SH-SY5Y细胞中，观察miR144/451在PD细胞中发挥的作用及机制。以期为PD的临床治疗提供新的靶蛋白。研究结果表明，miR144/451敲除对帕金森病小鼠模型有缓解作用，miR144/451可能通过下调氧化基因Sod1、GPX1、Cat等基因加重PD小鼠脑内氧化应激起调控作用。项目资助发表核心期刊文章2篇，SCI论文2篇，申请专利1篇，授权专利1篇，或会议优秀论文1篇，培养的研究生获挑战杯优秀奖1项。培养研究生2名，获江苏省科创项目1项。