糖尿病视网膜病变（Diabetic Retinopathy，DR）是糖尿病患者常见的微血管病变之一，严重威胁患者视觉功能。目前研究发现DR中有细胞衰老的发生，然而对于糖尿病如何引起细胞衰老及细胞衰老是否参与DR的发生发展并不清楚。申请人前期结果发现在DR中组蛋白H1.2及其赖氨酸甲基化修饰显著性上调。体内外过表达/敲低H1.2均能调控视网膜细胞衰老。高糖刺激减弱H1.2与Nucleolin相互作用并促进p53积累。据此提出“高糖刺激促进H1.2甲基化修饰，调控p53介导的细胞衰老，进而促进DR的发生发展”的假说。申请人拟采用1型糖尿病小鼠及视网膜细胞为研究对象，通过玻璃体注射AAV病毒介导的视网膜基因过表达和敲低及药物刺激等实验，研究H1.2及其甲基化修饰调控细胞衰老及DR的分子机制，探索治疗DR的潜在药物。本项目有望对DR分子机制提供新的理论基础，为缓解和治疗DR提供潜在的药物靶点。

Diabetic retinopathy (DR) is one of the most common microangiopathys in diabetes, which seriously threatens their visual function. Recent studies found that cell senescence happened in the diabetic retinas. However, how diabetes cause cell senescence and whether cell senescence contributes to the development of DR is not clear. Our preliminary work found that H1.2 and its lysine-methylation are increased in the diabetic retinas. Overexpression/knockdown of H1.2 regulate cell senescence both in vivo and in vitro. Moreover, high glucose treatment weakens the interaction between H1.2 and Nucleolin, and promotes the accumulation of p53. Therefore, we hypothesize that high glucose promotes H1.2 methylation, then regulates p53-mediated cell senescence and eventually contributes to the development of DR. We will investigate the regulatory mechanism of H1.2 and its methylation in the development of diabetic retinopathy through cell senescence, by using AAV-mediated genes overexpression/knockdown and drug treatment on type 1 diabetic mice and retinal cells. This project may provide new perspectives of DR development and potential new drug-treatment targets.