细胞衰老是引起器官退化性病变的主要原因之一，是细胞生物学的重要研究领域。糖尿病视网膜病变（糖网）具有典型的神经和血管退行性病变表征，为常见疾病，目前病变机制仍有待完善、治疗药物较缺乏。申请人前期发现组蛋白变体H1.2在糖网中发挥重要作用，工作2017年发表于Autophagy。在此基础上，申请人进一步发现组蛋白H1.2水平可影响DNA损伤信号通路和细胞衰老，相关研究尚未见国内外报道。申请人据此提出“H1.2是调控细胞衰老的新因子”工作假说。本项目拟采用基因敲除/过表达的细胞和小鼠模型，研究①H1.2通过PARP-1和/或线粒体功能来调控DNA损伤和细胞衰老的分子机制；②H1.2表达长期异常对糖网病变的影响；③咖啡因能否通过抑制组蛋白H1.2水平从而抑制细胞衰老和糖网病变。项目有望揭示H1.2调控细胞衰老而最终影响视网膜病变的分子机制，为糖网的防治提供新理论新方向。

Cellular senescence, an important field for cell biology, is one of main causes of organ senescence and leads to degenerative diseases. Diabetic retinopathy (DR), characterized with neuronal and vascular degeneration, is a common eye disease. At present, however, the mechanism underlying the development of DR remains unclear and effective drugs are lacking. The applicant recently reported that histone H1.2, a histone variant, plays an important role in the development of DR, and the result has been published in Autophagy. Further studying the underlying mechanism, the applicant found that H1.2 can affect the DNA damage response pathway and cell senescence, similar reports have not yet been found. The applicant hypothesizes that histone H1.2 is a new factor in regulating cell senescence. In this proposal, gene knockout / knockdown or overexpression cell and mouse models will be used to study following key scientific questions: ① The molecular mechanism of how histone H1.2 regulates DNA damage response and cell senescence through PARP-1 and/or mitochondrial function. ② The long-term effects of histone H1.2 overexpression or deficiency on the degenerative lesions in DR. ③ Whether caffeine can inhibit the degenerative lesions in DR by downregulating H1.2 and cell senescence. We expect to reveal the molecular mechanism of how H1.2 regulates cell senescence and ultimately affects the retinal neuronal and vascular degeneration, which may provide new theory and direction for the prevention or treatment of DR.