晶体后囊膜混浊（PCO）是人工晶体植入术后造成视力下降的最普遍后遗症，晶状体上皮细胞间充质转化（EMT）是其病理过程中的重要分子事件。AKT蛋白激酶参与转化生长因子TGFβ 诱导的晶状体上皮细胞EMT过程，但具体调控机制不明确。本项目以AKT蛋白激酶对组蛋白修饰酶EZH2和p300的磷酸化修饰为切入点，探索其介导的组蛋白修饰变化调控TGFβ诱导晶状体上皮细胞EMT的机制，将确立1）AKT-EZH2-H3K27me3和AKT-p300-H3/H4Ac通路对EMT基因转录调控的重要作用；2）AKT蛋白激酶异构体AKT1和AKT2差异性磷酸化EZH2和p300的分子机制，及由其介导的差异性H3K27me3和H3/H4Ac对EMT基因表达调控的影响；3）评介靶向H3K27me3和H3/H4Ac的小分子药物在PCO预防和治疗中的临床意义。项目的研究结论将为临床PCO药物的选择使用和研发提供新思路。

Posterior capsule opacification (PCO) is the most common complication after cataract surgery, causing vision impairment. EMT (Epithelial-Mesenchymal Transition) of the residual lens epithelial cells in the lens capsular bag is a major pathologic change during the development of PCO. Even though a few studies have pointed out the correlation between AKT kinase activation and TGFβ-induced EMT of lens epithelial cells, the underlying regulatory mechanisms remains unknown. In this project, we focus on the phosphorylation substrates of AKT kinases: EZH2 and p300, two important histone modification enzymes, and investigate the function of histone modifications controlled by AKT kinases in TGFβ-induced EMT of lens epithelial cells. Specifically, we aim to elucidate that 1) AKT-EZH2-H3K27me3 axis and AKT-p300-H3/H4Ac axis are important for the regulation of EMT gene expression. 2) The molecular mechanisms by which AKT kinase isoforms AKT1 and AKT2 differentially phosphorylate EZH2 and p300, as well as the consequence of differential H3K27me3 and H3/H4Ac modifications on EMT gene expression. 3) Evaluate the clinical significance of small molecules targeting H3K27me3 and H3/H4Ac modifications in PCO prevention and treatment. The obtained results will guide the application of the available epigenetic drugs for PCO, and provide novel information for the development of PCO therapeutic strategy.