纳米二氧化钛通过ROS/TRPM2/NLRP3炎症小体信号通路加剧溃疡性结肠炎的机制研究

随着纳米二氧化钛（TiO2 NPs）在药品和食品中的广泛应用，炎性肠病患者暴露TiO2 NPs的机率也大大增加，因此对TiO2 NPs在疾病状态下暴露的风险评估更值得关注。申请人前期研究发现，TiO2 NPs可引起正常小鼠肠道炎症，但其对本身处于炎症的小鼠或细胞影响尚不清楚。因此，本项目基于LPS诱导的炎症肠上皮细胞和DSS诱导的结肠炎小鼠，通过研究其细胞功能、氧化应激水平等探讨TiO2 NPs介导的ROS对其炎症的作用，并进一步通过RNAi、基因敲除等手段探究ROS对NLRP3炎症小体的调控作用以及TRPM2在ROS介导的NLRP3炎症小体中的调控作用及机制。综上所述，本项目拟从分子水平阐明TiO2 NPs加剧疾病状态下细胞和小鼠炎症反应可能的作用机制，以上机制的阐明，不仅为TiO2 NPs在特殊人群食品和药品中的安全应用提供理论基础，同时也为多致病因素肠炎疾病的干预提供潜在靶点。

With the wide application of TiO2 NPs in medicine and food, the probability of exposure of TiO2 NPs in patients with inflammatory bowel disease has also greatly increased. Therefore, risk assessment of TiO2 NPs in disease states is more worthy of attention. Our previous study found that TiO2 NPs can cause intestinal inflammation in normal mice, but its effect on inflamed mice or cells is unclear. Therefore, our study intended to use LPS-induced inflamed cells and DSS-induced colitis mice as model, and apply oxidative stress level measurement and biological function characterization to investigate the effects of TiO2 NPs-mediated ROS on inflammatory organisms. And further with assistant of RNAi or gene knock out methods to explore the regulatory effect of ROS on NLRP3 inflammasome, and in addition for the regulatory effect of TRPM2 in ROS-mediated NLRP3 inflammasome. In summary, the proposed research will provide new insights into understanding of the molecular mechanisms involved in TiO2 NPs intensifying the inflammatory response of inflamed cells and mice. This provides not only a theoretical basis for the safe application of TiO2 NPs in food and medicine for special populations, but also suggests potential targets for treatments of multi-pathogenic enteritis diseases.