具核梭杆菌致结直肠黏膜DNA损伤诱导炎症和促癌发生

结直肠癌（CRC）发生机制并未完全阐明。已知DNA损伤参与肿瘤发生，某些肠菌如具核梭杆菌在CRC发生发展中起促进作用。我们发表在CELL的论文证实该菌通过诱导自噬而引起CRC对化疗耐药。我们的预实验显示具核梭杆菌等主要参与CRC的肠菌可致肠黏膜DNA损伤、炎症和细胞增殖。但尚未明了肠菌紊乱-DNA损伤-肠黏膜炎症-癌发生的详细过程与机制，更不清楚其之间的网络调控情况。为此，本项目将在临床标本中分析该菌与DNA损伤相关基因表达关系；在Germ-free C57BL/6、联合用多种抗生素为小鼠去污等模式动物中，灌注该菌后观察DNA损伤和通路变化。体内外导入致DNA损伤或修复损伤的基因或蛋白，或封闭DNA损伤通路，或应用甲硝唑干预，分析小鼠和正常黏膜细胞生物学行为变化。本研究旨在阐释具核梭杆菌通过DNA损伤诱发炎症和CRC的通路及其机制，并有望为根除该菌而防治CRC提供实验依据。

The mechanism of colorectal cancer (CRC) has not been clearly elucidated. DNA damage is known to be involved in tumorigenesis, and the intestinal bacteria such as Fusobacterium nucleatum (F. nucleatum) promote the development of CRC. The article we have published in CELL confirmed that F. nucleatum could cause CRC to be chemo-resistant by inducing autophagy. Meanwhile our pilot trial showed that the intestinal bacteria majorly involved in CRC could lead to DNA damage, inflammation and cell proliferation. However, the detailed process, mechanism and even the regulatory network of dysbiosis-DNA damage-mucosal inflammation-cancer are not yet known. Thus, our project firstly plans to analyze the relationship between intestinal bacteria and the expression of DNA-damage-related genes. Secondly, we design to combine a variety of antibiotics for experimental mice decontamination to further perfuse bacteria or metabolite we are interested in, and then observe the change of DNA-damage proteins, genes and pathways. Then up- or down-regulation of related genes, proteins or pathways are done to analyze the biological process of experimental mice or normal mucosal cells. Through aforementioned methods, our project aims to clarify the pathways through which intestinal bacteria such as F. nucleatum induce inflammation and CRC, which is expected to provide experimental evidence for preventing and treating CRC by eradicating the bacteria.