肺癌是我国发病率和致死率最高的恶性肿瘤，尚无有效治疗方法，针对肺癌新型疗法的应用基础研究具有重要意义。通过生物信息学分析，我们发现DNA胸腺嘧啶糖基化酶（Thymidine DNA Glycosylase, TDG）在肺癌中的表达异常升高，并伴随患者生存期显著缩短，提示TDG可能是肺癌治疗和新药研发的重要靶点。前期工作显示，在肺癌细胞H1299和Calu-1中敲除TDG基因能显著抑制它们的增殖速度和裸鼠皮下成瘤能力。为探究TDG在肺癌发生发展中的作用及调控机制，本项目首先通过小鼠肺癌自发成瘤模型验证TDG是否对肺部肿瘤形成具有促进作用；其次，探讨TDG的促癌作用是否依赖糖苷酶活性；最后，通过研究TDG敲除对转录组及基因启动子区域DNA表观修饰的影响，找到TDG下游的靶点基因和信号通路。项目将深入揭示TDG调控肺癌发生发展的表观遗传机理，为明确TDG作为肺癌治疗的关键靶标提供充分的理论支撑。

It is imperative to develop novel therapies for treating lung carcinoma, the most prevalent cancer and the leading cause of death among all types of tumor in China. Through bioinformatic analysis, we found that the expression of Thymidine DNA Glycosylase (TDG) is significantly increased in the tumor section compared to the normal tissue. Patients with high expression of TDG had a reduced survival comparing to the ones with low expression, suggesting TDG may serve as novel target for therapeutic and drug development. We knocked out TDG using CRIPSR-Cas9 in several lung cancer cell lines and found that TDG KO inhibited cell proliferation and tumor formation in nude mice. To explore the regulatory function and mechanisms of TDG during lung cancer development and progression, we will first validate the oncogenic role of TDG using a spontaneous mouse model of lung cancer, then examine whether this function relies on the glycosylase activity of TDG, finally identify the downstream targets and effectors of TDG. This work aims to tackle two scientific questions: whether TDG is a potential therapeutic target in lung cancer and whether the mechanism behind is related to its glycosylase activity. Our research is expected to provide the epigenetic mechanism of TDG in regulating lung tumorigenesis and deliver preclinical evidence for developing TDG as a therapeutic target in lung cancer.