RNA甲基化调控小胶质细胞糖代谢在老年痴呆症发生发展中的作用和机制研究

老年痴呆症（Alzheimer’s disease, AD）是老龄化人口罹患的主要神经退行性疾病。小胶质细胞（Microglia, MG）的功能紊乱和AD的发生发展密切相关，近期研究发现MG糖代谢紊乱导致其功能紊乱，我们的前期工作发现通过调控MG的糖代谢可以改善AD的病理。RNA甲基化是一种重要的转录后表观调控机制，在神经系统的发育中起到重要的作用，但在AD病理过程的作用和机理尚未见报道。在前期工作基础上，我们推断RNA甲基化参与了MG糖代谢和功能的调控，在AD发生发展中起到重要的作用。我们将利用RNA甲基化研究的技术和组学的方法，在MG细胞和AD模型小鼠上，研究AD病理状态MG糖代谢紊乱的分子机理及其在AD发生发展中的作用，阐明RNA甲基化相关蛋白在AD中的变化以及对MG糖代谢和功能调控的机制，探索通过靶向MG糖代谢和RNA甲基化来干预AD的病理，为AD的诊治提供理论依据和新策略。

Alzheimer’s disease (AD) has been becoming a major ageing-associated neurodegenerative diseases. Among many identified cellular and molecular mechanism underlying the development of AD, microglial dysfunction has been shown to be tightly involved in the process and a potential therapeutic target in AD treatment. Even though many lines of evidence link microglial dysfunction with AD pathology, there remains to be elusive on the detailed mechanism. We and other groups have reported that strengthening microglial glucose metabolism could alleviate AD pathology, implicating a potential treatment avenue for AD. Recently, RNA methylation has been shown to play an important role in gene expression among different physiological and pathological processes, including the development and pathology of central nervous system. However, it is totally unclear about the role and mechanism of RNA methylation in the regulation of microglial function during AD development. Our pilot experiments suggest that RNA methylation might be involved in microglial dysfunction and glucose metabolic disorder. Here, by utilizing the state-of-art methods and techniques and combining with microglial cells and AD murine models, we aim to: 1) investigate the relationship between unbalanced microglial glucose metabolism and AD development; 2) define the role and mechanism of RNA methylation in the regulation of microglial glucose metabolism; 3) explore the potential therapeutic avenues for AD treatment by targeting microglial glucose metabolism and RNA methylation. Our proposal shall elucidate a novel regulatory mechanism of microglial dysfunction in the AD development and pave a new way for the diagnosis and treatment.