RNA甲基化修饰调控小胶质细胞功能在神经可塑性中的作用和机制研究

小胶质细胞在神经系统正常发育和稳态维持方面具有重要作用。近年来，mRNA甲基化修饰对mRNA的代谢和基因表达受到越来越多的关注，其中N6-甲基腺苷(m6A)是mRNA内含量最丰富的一种修饰。在神经系统内m6A修饰参与神经干细胞的增殖和分化，调控小鼠的情绪和学习记忆，但是m6A修饰在小胶质细胞中的作用还很不清楚。我们前期研究发现小胶质细胞Mettl3特异性敲除显著改变小胶质细胞的形态和炎症因子表达，引起小鼠神经元树突棘数目的变化，以及降低小鼠的学习认知能力。在此基础上，本项目将利用基因敲除小鼠，结合微量基因组学、双光子显微成像、质谱流式等技术，进一步明确RNA甲基化修饰在小胶质细胞功能调控中的作用，并深入研究在神经可塑性和学习认知中的作用和分子机制。本项目的顺利进行将进一步阐明小胶质细胞在神经系统功能维持中的作用和分子机制，同时为临床相关疾病的诊治提供潜在的治疗策略。

Microglia plays an important role in the normal development and homeostasis of nervous system. In recent years, more and more attention has been paid to the metabolism and gene expression of mRNA by methylation modification, among which N6-methyladenosine (m6A) is the most abundant modification in mRNA. In the nervous system, m6A modification shows to participate in the proliferation and differentiation of neural stem cells, and regulate the emotion, learning and memory of mice. However, the regulation of m6A modification in the function of microglia is not clear. Our preliminary results shows that microglial Mettl3 knockout significantly changed the morphology and the expression of inflammatory factors, and at the same time caused changes in the number of dendritic spines in neurons of mice, as well as decreased learning and cognitive ability of mice. Basis on these results, we will use transgenic mice, microgenomics and mass spectrometry technologies to further study how RNA methylation can regulate microglia function, and how to regulate neural plasticity and learning cognitive ability. This project will further clarify the role and molecular mechanism of microglia in the maintenance of nervous system function, which will provide potential intervention targets and new treatment strategies for the diagnosis and treatment of clinical cognitive disorders related diseases.