纳米二氧化硅低水平暴露诱发肺部炎癌转化及其调控机制研究

结晶型二氧化硅可引起职业人群矽肺和肺癌，国际癌症研究机构将其定为人类确定致癌物，但人群暴露机会更多的无定型纳米二氧化硅的致癌性目前尚无定论。本课题组前期发现，无定型纳米二氧化硅可诱发慢性炎症，导致细胞恶性转化，但其分子机制尚不清楚。本项目从细胞、动物和人群层面系统研究无定型纳米二氧化硅低水平暴露对自噬功能、慢性炎症、p53网络和基因组不稳定性及细胞恶性转化的影响。构建自噬缺陷型Atg7和p62转基因动物模型和细胞模型，分析无定型纳米二氧化硅经自噬信号通路和p53网络对慢性炎症和炎癌转化的调控机制。利用毒理基因组学技术高通量筛选炎癌转化生物标志物，采用硅稳定同位素示踪技术评估职业人群暴露水平，病例对照研究分析人群肺功能并进行生物标志物人群验证，分析比较不同晶体结构二氧化硅致癌作用及机制的差异，阐明纳米二氧化硅致炎癌转化的分子机制。为纳米材料安全性评价和肿瘤风险评估及肿瘤综合防治提供科学依据。

Crystalline silica can cause silicosis and lung cancer in occupationally exposed people. It has been identified as a carcinogen by the IARC. However, the carcinogenicity of amorphous silica nanoparticles with more exposure opportunities in the population is still uncertain. Our previous studies have indicated that amorphous silica nanoparticles could induce chronic inflammation and malignant transformation of cells, but its molecular mechanism is still unclear. This research will combine cellular, animal and population based studies to systematically investigate the effects of low-level exposure to amorphous silica nanoparticles on autophagy, chronic inflammation, p53 network, genomic instability, and malignant transformation of cells. Autophagy-deficient Atg7 and p62 gene conditional knockdown animal models and cell models will be used to analyze the regulatory mechanism of amorphous silica nanoparticles on chronic inflammation and malignant transformation through autophagy signaling pathway and p53 network. In order to analyze and compare the carcinogenicity and mechanism of silica nanoparticles with different crystal structures, silicon stable isotope tracer technique was used to assess the exposure level of occupational population, toxicogenomics was used to screen high-throughput biomarkers related to the inflammation carcinogenesis transformation, and case-control study was used to verify the biomarkers in occupational population. Finally, the present research will elucidate the molecular mechanism of inflammation carcinogenesis transformation induced by silica nanoparticles, and will provide scientific basis for safety assessment and health risk assessment of nanomaterials and comprehensive prevention and treatment of cancer.