DYRK1A通过KAT6A重塑染色质在放疗肺纤维化中的作用及机制研究

经胸放射治疗是临床常用的局部治疗手段之一，既往研究提示接受外照射的肺癌患者约5%-15%发生了放射性肺炎。放射性肺炎急性期尚可通过激素等药物处理控制病情，但远期纤维化将不可逆转。肺纤维化时，成纤维细胞的激活是核心事件，因此，及时的控制成纤维细胞的激活是控制放疗后肺纤维化损伤的关键。本项目前期研究发现肺成纤维细胞DYRK1A表达在放疗后明显上调，成纤维细胞特异敲除DYRK1A将显著抑制放疗后肺纤维化损伤。通过ChIP-Seq高通量筛选，我们发现DYRK1A可通过重塑组蛋白H3K27ac修饰，从而靶向成纤维细胞激活相关基因的启动子影响其转录。进一步的蛋白质谱提示，DYRK1A调控H3K27ac修饰，是通过结合KAT6A，抑制其降解，从而实现的。本项目旨在探索DYRK1A通过KAT6A调控成纤维细胞激活的作用及机制，为防治放射性肺炎肺纤维化提供新的方向。

Transthoracic radiotherapy is one of the commonly used local treatments in clinic. Previous studies had shown that about 5% - 15% of lung cancer patients receiving external irradiation had radiation pneumonitis. The acute stage of radiation pneumonitis can be controlled through hormone or other drugs, while the fibrosis would be irreversible. The activation of fibroblasts is the core event in pulmonary fibrosis. Therefore, timely and effectively control of fibroblast activation is the key of preventing pulmonary fibrosis after radiotherapy. Previous results of this project remind that the expression of DYRK1A was significantly up-regulated in lung fibroblast after radiotherapy.Fibroblast specific knockout of DYRK1A would significantly inhibit pulmonary fibrosis after radiotherapy. Through high-throughput ChIP-Seq, we found that DYRK1A could target fibroblast activation related gene promoters and affect their transcription by remodeling histone H3K27ac. Protein mass spectrometry indicated that the regulation of DYRK1A on H3K27ac was mediated by binding and protecting KAT6A from degradation. This project aims to explore the role and the related mechanism of DYRK1A in regulating fibroblast activation through KAT6A, also aim to provide a new direction for the prevention and treatment of radiation pneumonitis and pulmonary fibrosis.