microRNA与新生鼠缺氧缺血脑损伤的细胞自噬调控

项目名称： microRNA与新生鼠缺氧缺血脑损伤的细胞自噬调控

项目编号： No.81330016

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 母得志

作者单位： 四川大学

项目金额： 290万元

中文摘要： 新生儿缺氧缺血性脑病（HIE）是引起新生儿死亡和儿童致残的重大难治性疾病，探索HIE损伤与修复机制意义重大。研究表明，自噬是参与缺氧缺血(HI)后神经损伤的重要因素。前期工作中，我们用表达谱芯片筛查新生鼠HI脑组织基因差异表达，发现自噬相关基因LC3、Beclin1、Atg10及Atg16L明显上调。经生物信息学分析发现，靶向调控这些自噬基因的微小RNA（microRNA）与芯片筛查发现新生鼠HI脑组织差异表达的microRNA有重叠。因此，推测特异性 microRNA的表达是调控HI后自噬的重要机制。本课题将研究与新生鼠HI脑损伤相关调控自噬的关键microRNA分子，探明调节这些microRNA表达的信号通路。同时，将利用microRNA分子具有高稳定性和组织相容性的特点，通过体内外实验，探索microRNA分子抑制新生鼠HI脑损伤的新方法，为临床治疗新生儿HIE提供新思路。

中文关键词： 新生儿;缺氧缺血;脑;自噬;微小RNA

英文摘要： Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe disease that can cause high mortality and disability in newborns. Therefore, it is very important to explore the mechanisms underlying HIE and the repairing mechanisms after hypoxic-ischemic injury. Autophagy has been documented as a key factor to regulate neural injury induced by hypoxia-ischemia in neonatal rats. We have previously demonstrated that several autophagy-related genes, such as LC3, Beclin1, Atg10, and Atg16L, were up-regulated significantly, using microRNA chip to screen the differential expression of genes in brain tissues of hypoxic-ischemic and sham control neonatal rats. Based on the bio-informatic study, we found that microRNAs targeting autophagy-related genes overlap with the microRNAs identified by microRNA chip screen in our perliminary studies. Therefore, we hypothesize that the effect of specific microRNAs plays a key role in the mechanisms of pathologic changes and self-repair by regulating autophagy after hypoxic-ischemic brain damage. In this project, we will try to study the key microRNAs that target autophagy-related genes and elucidate the signaling pathways regulating the expression of autophagy-related microRNAs. Due to the stable and high tissue compatibility characteristics of microRNAs, we will also try to explore the feasibility of using microRNAs to inhibit hypoxic-ischemic brain damage using a neonatal rat model to mimic newborns with HIE in clinic. This work will provide a new method to treat and prevent HIE.

英文关键词： neonate;hypoxia-ischemia;brain;autophagy;microRNA