microRNA-425调控坏死性凋亡介导多巴胺能神经元变性的机制研究

作为最常见的一种神经退行性疾病，帕金森病(Parkinson's disease, PD)的发病机制目前尚未完全阐释清楚，而我们前期的研究发现，坏死性凋亡可能在多巴胺能神经元变性中发挥了重要作用，参与了PD的发病。因此，寻找并研究启动坏死性凋亡的相关上游信号渴望为PD的机制研究及诊疗带来新的进展。通过生物学信息预测及测序分析，我们发现，作为调控坏死性凋亡关键蛋白RIPK1基因表达的miRNA-425，可能参与多巴胺能神经元变性的发生。为了验证该假说，我们构建了miRNA-425敲除的小鼠，来模拟在衰老和PD过程中miRNA-425的丢失，并通过离体和在体实验进一步明确miRNA-425在PD发病机制中的作用及其分子机制，尤其是与RIPK1的表达以及多巴胺代谢和坏死性凋亡信号通路的关系；同时探讨外源性miRNA-425治疗PD动物模型的可能。

Parkinson’s disease (PD) is one common neurodegenerative disorder, and the pathogenic mechanisms of PD are not completely confirmed so far. According to our previous study, necroptosis is thought to play a key role in the neurodegeneration of dopaminergic neurons and take part in the developing of PD. Therefore, seeking the upstream molecular which triggered Necroptosis via regulation of RIPK1 could prompt the research progress for PD. With miRNA predicting system and sequencing (miRNA-seq) with SNpc tissue of MPTP, we put forward that mir-425 involve the neurodegeneration of dopaminergic neurons via regulation of RIPK1. For validation the hypothesis, we plan to develop the miRNA-425 conditioned knockdown mice model, and observe the deficiency of miRNA-425 following the aging and PD pathology; and then reveal the mechanism in details of miRNA-425 involvement of dopaminergic neurodegeneration via necroptosis associated molecular, RIPK1. Meanwhile, we plan to identify brain delivery of miRNA-425 as a potential therapeutic approach for the treatment of PD.