miR-17-92基因簇调控神经干（前体）细胞移植后分化的机制研究

项目名称： miR-17-92基因簇调控神经干（前体）细胞移植后分化的机制研究

项目编号： No.31471019

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 神经、认识与心理学

项目作者： 李靓

作者单位： 南京大学

项目金额： 85万元

中文摘要： 在神经干（前体）细胞（NSPCs）移植治疗神经系统损伤或疾病的研究中，NSPCs分化形成神经元的比例较低，影响了移植后的治疗效果。研究显示，神经系统损伤或疾病，以及细胞移植均会引起神经炎症反应，激活内源性胶质细胞，释放细胞因子如LIF，CNTF等。上述因子信号通路的激活会促进NSPCs向星形胶质细胞分化，减少神经元的比例。我们的研究提示miR-17-92基因簇能抑制LIF，CNTF等因子信号通路中多个关键蛋白，阻断相关信号通路的激活。由此我们假设，神经炎症环境下产生的细胞因子影响了NSPCs移植后的分化命运，导致神经元分化数量不足；用miR-17-92早期干预NSPCs，可以阻断细胞因子对NSPCs分化的影响，提高神经元的分化比例，改善细胞移植的治疗效果。该研究有助于我们阐明神经炎症环境影响NSPCs分化的分子机制并寻找有效的干预手段，为细胞移植治疗神经系统损伤和疾病的研究提供了新的思路。

中文关键词： 神经干(前体)细胞；神经炎症；细胞因子；细胞分化；miR-17-92基因簇

英文摘要： Neural Stem/progenitor cells (NSPCs) transplantation is a promising strategy for neurodegenerative diseases and brain injury. However, the low yield of NSPC-derived neurons hampers their potential for neuronal replacement. Circumstantial evidence suggests that neuroinflammation is usually aroused during the process of diseases or injury, even after cell replacement. The inflammation environment causes the activation of endogenous glia cells that release cytokines such as LIF or CNTF, which further facilitate astrogenesis, thus reducing the neuronal differentiation from NSPCs. Our study indicates that miR-17-92 cluster, which has multiple targets related to the signaling pathway of those cytokines, may block the effect of these molecules on cells. Therefore, we proposed that cytokines produced during neuroinflammation affect the differentiation of NSPCs, causing the low yield of NSPCs derived neurons. Overexpression of miR-17-92 can block the effect of cytokines on the differentiation of NSPCs, which increases the ratio of neuronal differentiation and improves brain lesions after cell transplantation. This project not only helps us to elucidate the mechanism underlying the neuroinflammation affected NSPCs differentiation but also provides us with new venues for cell replacement therapy for neurodegenerative diseases and brain injury.

英文关键词： neural stem/progenitor cells;neuroinflammation;cytokine;differentiation;miR-17-92 cluster