NF-κB反复激活介导的口腔菌群-代谢改变在鼻咽癌放疗致放射性口腔黏膜炎损伤中的作用机制研究

Radiation oral mucositis is a common radiation injury among nasopharyngeal carcinoma patients during and after radiation therapy, which influencing compliance and life quality of patients strongly. However,the pathogenesis of radiation oral mucositis , which is complicated and unclear, has poor response to treatment. In the pre-experiment, we found irradiation was significantly related with the changes of metabolite in saliva of patients who received radiation therapy.Due to the recent studies, we hypothesize that “Repeated NF-kappaB activation → Oral microflora imbalance → Metabolite changes” is occurred during radiation oral mucositis. Based on preliminary results, the Electrophoretic Mobility Shift Assay is used to study the activity of NF-kappaB, a next generation sequencing platform of oral microbiota is established to analyze oral microflora structure, and an untargeted metabonomics platform of biological specimens is used to clarify the characteristics of oral microbiota function. We will verify the hypothesized mechanisms and establish a prediction/diagnosis model for radiation oral mucositis based on metabonomics. This study that based on the research of oral mucositis will provide us important clinical significance.

放射性口腔黏膜炎（ROM）是鼻咽癌根治性放射治疗期间及治疗后常见的放射性损伤，严重影响患者治疗依从性及生活质量。其发病机制复杂，至今尚未明确，因此治疗效果不佳。在预实验中我们发现，鼻咽癌患者放疗中唾液代谢产物的变化与电离辐射紧密关联。根据前期研究成果，我们提出假说：放射性口腔黏膜炎发生存在“NF-κB反复激活→口腔菌群失调→代谢产物改变”的作用机制。为了验证该假说，本项目拟在前期研究的基础上，采用 EMSA法检测ROM进程中NF-κB活化程度，利用口腔菌群二代测序方法分析口腔菌群结构，利用代谢组学方法了解ROM进程中口腔菌群功能的特征变化。在验证假说的同时，我们将建立基于代谢组学的ROM预测、诊疗评估模型。该ROM相关研究项目具有重要的临床意义。

放射性口腔黏膜炎（ROM）是鼻咽癌根治性放射治疗期间及治疗后常见的放射性损伤，严重影响患者治疗依从性及生活质量。其发病机制复杂，至今尚未明确。项目组首先检测了ROM发生过程中人群唾液NF-κB的表达量，证实其成上升趋势，验证了NF-κB 存在反复激活的现象。随后，项目组对唾液标本进行了代谢组学检测，结果表明：在肿瘤发生时期，代谢物的变化更多的与合成有关，而在ROM进展变化的过程中代谢物及通路变化更多的展现了炎症和肿瘤综合作用的结果。项目组通过对结果的差异及富集分析绘制出相应的ROM 辐射损伤-代谢谱。最后，项目组运用影像组学的纹理分析手段对于ROM前后人群的腮腺MR进行了分析，同时与代谢组学数据进行分析，证实了相对易得到的影像学数据可以反映唾液代谢组学的变化情况，并通过多模态组合可以更好地反映患者ROM的情况，建立完整的分析模型。通过项目研究，项目组验证了“NF-κB 反复激活→代谢产物改变→影像数据改变”科学假说，实现了”临床现象→机制研究→临床实用“的转化，掌握了鼻咽癌根治性放疗致ROM中NF-κB活化程度及多模态组学转化情况，刻画了基于口腔的辐射损伤多模态图谱；阐述了鼻咽癌根治性放疗所致ROM的辐射损伤机制，筛选出可以反映损伤演变的特异性分子标记物及影像组学特征，构建了ROM疾病预测及诊疗评价体系。