LncRNA Kcnq1ot1介导DGCR8的SUMO1修饰调控神经元凋亡的机制研究

非编码RNA特别是lncRNA和miRNA在阿尔茨海默病(Alzheimer's disease,AD)神经元凋亡中具有十分重要的作用。但是，lncRNA通过何种途径调控miRNA，是迫切需要解决的前沿科学问题。我们的前期研究证实，lncRNA Kcnq1ot1可以调控神经元miR-296的水平，并且Kcnq1ot1在细胞质和细胞核中均有表达。据此我们提出如下假说：胞核中Kcnq1ot1通过调控RNA结合蛋白-DGCR8的SUMO1修饰过程，影响DGCR8与pri-miRNA-296的结合，导致miR-296生成减少；而胞质中Kcnq1ot1通过竞争性吸附miR-296，解除miR-296对Bax的抑制作用，最终促进神经元凋亡。为证实上述假说，我们将采用一系列分子生物学方法，通过体内、体外实验，拟从非编码RNA相互调控这一角度探索AD的发病机制，为寻找有效的防治靶点提供新的思路。

Non-coding RNA, especially lncRNA and miRNA, plays an important role in neuronal apoptosis in Alzheimer's disease (AD). However, the way in which lncRNA regulates miRNAs is a cutting-edge scientific problem which needs to be solved urgently. Our preliminary experiments has confirmed that lncRNA Kcnq1ot1 can regulate the level of miR-296 in neurons, and Kcnq1ot1 is expressed in both cytoplasm and nucleus. Therefore, we propose the hypothesis that Kcnq1ot1 in the nucleus affects the binding of DGCR8 to pri-miRNA-296 by regulating the SUMO1 modification of RNA binding protein-DGCR8, resulting in a decrease in the production of miR-296; whereas Kcnq1ot1 in the cytoplasm competitively adsorbes miR-296 to relieve the inhibitory effect of miR-296 on Bax and ultimately promotes neuronal apoptosis. We will confirm the hypothesis mentioned above by using a series of molecular biology methods in vivo and in vitro experiments, and explore the pathogenesis of AD from the perspective of non-coding RNA mutual regulation, and provide new ideas for finding effective targets for prevention and treatment.