PGC1A/ROS/p53信号轴调控胃黏膜逆生细胞命运及胃癌发生的作用及机制研究

胃癌是发病率及死亡率均居前列的恶性肿瘤，阐明其发病过程及分子病理学机理具有重要意义。在前期研究中，我们基于癌前病变的研究首次提出“逆生”新概念，细胞逆生是分化成熟细胞修复损伤的重要保守机制，完整无误的逆生对维持细胞健康及组织损伤修复尤为重要。为进一步阐明逆生的调控机制，本研究中我们提出在逆生细胞恶性转化及胃癌发生过程中，PGC1A表达异常引起的氧化还原状态变化可能对逆生细胞造成重要影响，通过调控恶性转化及胃癌发生关键靶细胞命运影响癌前病变及胃癌发生过程。本课题将以急性胃黏膜损伤动物模型及类器官体外培养模型为基础，通过高通量测序结合生物信息学分析、分子生物学技术及小动物化学诱导自发胃癌模型等手段，系统深入地研究并阐明逆生关键调节因子PGC1A介导氧化还原状态影响p53进而调控胃黏膜逆生细胞命运、组织损伤修复及胃癌发生的作用及分子机制，将为揭示细胞恶性转化及胃癌发生提供理论依据。

Gastric cancer is one of the malignant tumors with high morbidity and mortality in the world wild. It is of great significance to clarify the pathogenesis and molecular pathology of gastric cancer. In the previous research, we firstly proposed a new concept as "paligenosis" based on the study of precancerous lesions. Paligenosis is an important conservative mechanism for differentiated mature cells to repair damage. Unmistakable paligenosis is especially important for maintaining cell health and repairing tissue damage. In order to further clarify the regulatory mechanism of paligenosis in the present study, we suppose that during the malignant transformation of normal cells and the occurrence of gastric cancer, the redox state changes caused by abnormal expression of PGC1A may have an important impact on the paligenosis cells and could regulate the fate of key target cells to affect malignant transformation and gastric cancer occurrence. This project will be based on gastric mucosal acute injury model and gastric organoids model, high-throughput sequencing combined with bioinformatics analysis, molecular biology technology, mouse chemistry spontaneous gastric cancer models, to systematically research and clarify the role and molecular mechanism of the key regulator PGC1A, which mediates redox status and affects p53, and regulates gastric mucosal cell fate, tissue damage and repair, and gastric cancer. It will provide a theoretical basis for revealing cell malignant transformation and gastric cancer occurrence.