Hsf4转录调控自噬促进晶状体终末分化的分子机制

晶状体分化过程中纤维细胞清除细胞器的机制是悬而未决的科学问题，该过程障碍导致先天性白内障。Hsf4为热休克因子家族成员，其突变导致先天性白内障，但致病机制并不完全清楚。我们前期结果发现：1）Hsf4突变小鼠和敲除斑马鱼晶状体中纤维细胞的细胞器降解障碍；2）Hsf4缺失晶状体中自噬降解功能下降，Hsf4敲除的晶状体上皮细胞中自噬流减弱；3）转录组测序发现Hsf4突变鼠晶状体中部分自噬相关基因表达下降。因此，我们认为晶状体中Hsf4通过转录调控自噬基因的表达介导自噬过程，进而促进纤维细胞分化中细胞器的降解。本项目拟利用Hsf4缺失动物模型及细胞系研究：1）Hsf4介导的自噬在晶状体纤维细胞细胞器清除中的作用；2）Hsf4转录调控自噬的详细分子机制；3）干预自噬对Hsf4缺失导致的先天性白内障的治疗作用。通过本项目研究，阐明自噬在晶状体终末分化中的作用，为研发Hsf4相关白内障的药物提供新方向。

The mechanism regarding to clearance of organelles during lens differentiation is still ambiguous. Failures in clearance of organelles lead to congenital cataract formation. Hsf4 belongs to heat shock factor family, and its mutations cause inherited congenital cataract. However, the detailed pathogenesis how Hsf4 mutations lead to cataract is also unknown. Our previous results suggested that Hsf4 mutated mice and knockout zebrafish fail to degrade the organelles of lens fiber cells during lens differentiation. The autophagic degradation function decreased obviously in Hsf4 deficient lens, while the autophagic flux is reduced in Hsf4 knockout lens epithelial cells. Meanwhile, the expression levels of some autophagy related genes decreased in Hsf4 mutated mice lens. We speculate that Hsf4 transcriptionally activates to promote clearance of lens fiber organelles during lens differentiation. Using Hsf4 deficient animal models and lens epithelial cell lines, we aim to investigate the function of Hsf4 mediated autophagy during removal of lens fiber organelles. We also study the detailed mechanism about how Hsf4 transcriptionally regulated autophagy. The therapeutic effect of autophagic reagents in Hsf4 related congenital cataract will be also investigated. This study will reveal the role of autophagy during lens terminal differentiation and shed light on drug development for Hsf4 related congenital cataract.