FTO介导的m6A修饰通过调控巨噬细胞极化参与糖尿病视网膜血管病变的作用机制研究

巨噬细胞极化是巨噬细胞在不同微环境下的表型和功能分化，即M1和M2型，参与众多代谢性疾病发生、发展和转归。m6A-RNA甲基化(m6A RNA methylation)修饰是一种新型和广泛存在的基因调控方式，其调控异常影响许多疾病进程。然而m6A修饰能否通过调控巨噬细胞极化继而影响糖尿病视网膜血管病变，迄今未见报导。预实验发现，m6A修饰关键酶FTO在巨噬细胞极化和糖尿病视网膜中表达异常，且FTO干预影响巨噬细胞极化标记基因表达。本项目拟建立巨噬细胞极化模型和糖尿病动物模型，揭示FTO表达与巨噬细胞极化的相关性；明确FTO在巨噬细胞极化和视网膜血管病变的调控作用；阐明FTO调控巨噬细胞极化影响视网膜血管病变的分子机制；最后挖掘FTO及其介导通路作为糖尿病视网膜血管病变早期诊断和预后评估的临床价值。研究有望揭示糖尿病视网膜病变的调控新机制，为糖尿病视网膜病变的防治提供新策略。

Macrophage polarization refers to a process that experiences the switch of phenotype and function from M1 macrophages into M2 macrophages, which is involved in the occurrence, development, and return of several metabolic disorders. N6-methyl-adenosine (m6A) modification is a novel and widely existed gene regulatory mechanism. Its dysregulation is involved in the pathogenesis of several human disorders. However, the role of m6A in macrophage polarization and subsequence diabetic retinal vascular dysfunction is unclear. Our previous study has revealed that the m6A eraser, FTO, is down-regulated in macrophage polarization and diabetic retinas. Its intervention affects the expression of macrophage polarization-related genes. In this study, we will build macrophage polarization model and diabetic mouse model, detect the expression pattern of FTO in macrophage polarization, clarify the role of FTO in macrophage polarization and subsequent retinal vascular dysfunction through in vitro or in vivo intervention, reveal the molecular mechanism of FTO-mediated macrophage polarization through bioinformatics and molecular technique, and excavate the diagnosis and prognostic value of FTO and its related signalling in diabetic retinal vascular dysfunction. This study will provide a novel insight into the mechanism underlying diabetic retinopathy and a new target for the prevention and treatment of diabetic retinopathy.