RNA甲基转移酶METTL3调控小胶质细胞可塑性介导葡萄膜炎发生的机制研究

葡萄膜炎是我国常见而重要的免疫性致盲眼病，此病的发生与维持眼内微环境稳态的小胶质细胞功能失调密切相关，然而后者调控机制尚不清楚。基于此，我们开展的EAU模型初步研究发现METTL3可能调控小胶质细胞的功能，同时影响Notch通路关键基因的功能，提示METTL3可能通过激活炎症通路介导葡萄膜炎的发生。为深入阐明m6A表观转录修饰介导葡萄膜炎发生的机制拟进行下列研究: 1)通过体内外过表达及敲除实验探讨METTL3影响小胶质细胞的可塑性及介导葡萄膜炎发生的作用，以期阐明m6A修饰在葡萄膜炎发生中的作用；2)通过RNA-seq、MeRIP-seq等探讨METTL3调控Notch通路基因表观转录修饰的作用机制，以期阐明表观转录修饰介导葡萄膜炎发生的分子机制；3)通过高通量筛选发现靶向表观转录修饰的化合物。本研究将可能阐明表观转录修饰介导葡萄膜炎发生的机制和发现靶向化合物，为该病的精准治疗奠定基础。

Uveitis is an important immune-related vision-threatening and a common seen disease in China. Its occurrence is closely related to the imbalance of the ocular immune microenvironment. Microglia is the resident immune cells in the eye, which constituted the key network of homeostasis of intraocular microenvironment, and also the key factor of the development of uveitis. Based on these facts, our primary study found that RNA methylation (METTL3) may regulate the plasticity of microglia and affects the function of key genes in Notch pathway, suggesting that it plays an important role in the development of uveitis. In order to elucidate the mechanism of transcription modification in the development of uveitis, the following studies were carried out: 1) To define the effects of METTL3 on microglia plasticity in the development of uveitis via in vivo and in vitro studies; 2) To determine the mechanism of METTL3 regulating epigenetic transcription modification of the genes on Notch pathway via RNA-Seq and MeRIP-Seq etc; 3) To discover the small molecular compounds of uveitis targeting the transcription modification including METTL3 by high-throughput screening methods. Together, these experiments will provide insight into how is the mechanism of transcription modification mediated the development of uveitis and discover the targeting compounds for uveitis. The completion of these aims will provide the foundation for the precise treatment of uveitis and the related diseases.