lncRNA-Hser通过Oasis调控HIBD新生小鼠脑内胶质微环境的作用研究

Excessive astrogliosis is a key factor that hinders nerve regeneration in the brains of HIBD neonatal mice, but its mechanism is unknown. Using lncRNA microarray combined with the super-enhancer (SE) sequence analysis, we found that the expression of the SE-related lncRNA-Hser (Hser) was significantly increased especially in the glial scar region of neonatal mouse brain after HIBD. Interference with Hser expression can reduce the degree of gliosis and infarct size, and promote nerve regeneration. The expression of the ASCs specific transcription factor Oasis was also decreased, suggesting that Hser may remodel the glial microenvironment after HIBD through Oasis. Its exact molecular regulatory mechanism needs to be further demonstrated. This project is aimed to clarify①changes of the expression and distribution of Hser after HIBD; ②the functions of Hser in the reactive astrogliosis and scar formation; ③molecular mechanism that Hser activates Oasis; ④the downstream gene regulatory network of Hser, and its role in the glial microenvironment after HIBD. Completion of this project will have very important theoretical and clinical significance for revealing the role of lncRNA in neonatal HIBD and for designing specific nucleotide drugs.

过度胶质化是阻碍HIBD新生小鼠脑内神经再生的关键因素，但其作用机制不明。我们利用lncRNA芯片技术结合超强子（SE）序列分析筛选发现，SE相关lncRNA-Hser在HIBD新生小鼠脑组织，特别是反应性星形细胞（ASCs）胶质化和瘢痕区域表达显著增高。干扰Hser表达可以减轻组织胶质化程度和梗死面积，促进神经再生；ASCs特异性转录因子Oasis的表达也随之下调，提示Hser可能通过Oasis参与HIBD后胶质微环境的重塑。本项目拟在此基础上①明确Hser在HIBD的表达变化；②观察Hser在HIBD后反应性胶质化,特别是瘢痕形成的作用；③探讨Hser通过激活Oasis，调控反应性ASCs的分子机制；④初步建立Hser下游的基因表达调控网络，明确其在HIBD后胶质微环境的作用。课题的完成将对揭示lncRNA在新生儿HIBD中的作用及设计特异的核苷酸药物具有重要的理论价值和临床意义。

我们利用lncRNA芯片技术结合超强子（SE）序列分析筛选发现，SE相关lncRNA-Hser在HIBD新生小鼠脑组织，特别是反应性星形细胞（ASCs）胶质化和瘢痕区域表达显著增高。本课题对此深入研究，证实了干扰Hser表达可以降低组织胶质化程度和梗死面积，促进神经再生；ASCs特异性转录因子Oasis的表达也随之下调。我们证实了Hser和Oasis存在直接的相互作用，检测出Hser对Oasis的转录起调控作用，能够使Oasis表达上调；通过拯救实验观察到Hser在反应性ASCs的生物学作用得到了逆转。课题的完成对揭示lncRNA在新生儿HIBD中的作用及设计特异的核苷酸药物具有重要的理论价值和临床意义。