非小细胞肺癌（NSCLC）占肺癌总数的85%，是肺癌死亡的主要原因。由于目前靶向NSCLC血管新生的药物存在显著的副作用，导致其仅限于部分肺癌病人使用。为找寻到新的靶点，本课题针对NSCLC存在的KEAP1-NRF2信号通路的高频突变，将探索过表达转录因子NRF2可能介导的NSCLC血管新生机制。申请人前期通过基因芯片筛选出NRF2潜在调控的血管新生基因Angiogenin (ANG)，并通过实验初步证实了该ANG启动子区存在能与NRF2结合的ARE样序列。接下来，申请人将从基因分子生物学水平具体阐述NRF2对ANG的转录调控机制，并借助Crispr-Cas9技术分别从细胞生物学和动物学两个角度阐明NRF2是如何通过ANG实现对NSCLC血管新生的调控，进一步揭示NRF2/ANG信号通路在NSCLC血管新生中的作用。

Non-small cell lung carcinoma (NSCLC) accounts for 85% of all lung cancers and is the leading cause of lung cancer death. Due to the significant side effects, the current NSCLC drugs that targeting angiogenesis are limited to part of lung cancer patients. In order to find new strategy, the applicant took consideration of the high frequency mutation of KEAP1-NRF2 signaling pathway in NSCLC and screened the possible targeted angiogenesis-genes by transcription factor NRF2, and found Angiogenin (ANG). To further reveal how the transcription factor NRF2 regulates ANG transcription and thereby mediates NSCLC angiogenesis, the applicant designed this subject. In the previous work, the applicant found an ARE-like sequence in the ANG promoter region which might bind to NRF2, and this conjecture was confirmed by preliminary experiments. Next, the applicant will elaborate the transcriptional regulation mechanism of NRF2 on ANG from the level of gene molecular biology. Meanwhile, the applicant will further clarify how NRF2 regulates NSCLC angiogenesis via ANG and reveal the role of the NRF2/ANG signaling pathway in NSCLC angiogenesis from the aspect of cell biology and animal with the help of Crispr-Cas9 technology.