口腔扁平苔藓基于免疫调控网络的分子分型与个体化治疗研究

A breakthrough was made recently in disease molecular stratification and activity monitoring, based on the individual immunoregulatory network (Cell,2016). More multi-center evidence is needed prior to establishing a protocol for general applicability (Nat Rev,2016). Oral lichen planus (OLP) is the representative non-malignant condition of the oral mucosa. The heterogeneity of clinical characteristics, pathological manifestations and therapeutic effect of OLP are quite conspicuous, with the abnormality of immune regulation. So the hypothesis was presented that personalized immunomonitoring uncovers molecular networks that stratify OLP could be carried out based on our good foundation of immune regulation and big data analysis. To confirm that, firstly, clinical follow-up cohort of three centers will be enriched, and patients will be separated into independent training and test sets for validation. Secondly, Omics data of training set will be collected and analysed. Combined with the clinical traits, we will leverage weighted gene co-expression network analysis (WGCNA) to establish molecular stratification model, which would be supported by test set. Finally, immunological mechanism of different subtypes will be verified through the cell biology experiment. We could make the tailored therapeutic interventions for different subtypes. This study not only helps implement the concept of “Precision Medicine”, but also provides a model of general applicability of cutting-edge research strategy.

据个体化免疫调控网络对免疫相关疾病行分子分型和活动度监测获新突破(Cell,2016)，但该策略的普遍适用性需经多中心、研究更多疾病验证(Nat Rev Nephrol,2016)。口腔扁平苔藓(OLP)为常见非恶性口腔黏膜疾病的代表，其临床、病理及疗效异质性明显，且免疫调控网络异常，亟需更精细的分子分型。我们假定，结合申请组既往OLP免疫调控及大数据挖掘的良好基础，能实现其分子分型、制定个体化治疗方案。为此，国内三个国家临床重点专科团队联合，拟首先完善三中心临床随访队列，分别入组研究队列与验证队列；继之收集与分析转录组表达谱，结合临床随访资料，在研究队列构建加权网状统计模型，获分子分型，制定不同亚型个体化治疗方案，经验证队列前瞻印证；最后，通过细胞生物学实验分析促成不同亚型形成和发展的免疫学新机制。研究既有助于在口腔黏膜病学领域践行精准医疗理念，也为验证前沿研究策略的普遍适用性提供范例。

口腔扁平苔藓(OLP)为常见非恶性口腔黏膜疾病的代表，其临床、病理及疗效异质性明显，且免疫调控网络异常，亟需更精细的分子分型。为此，项目根据研究计划主要开展了临床队列的丰富与完善、组学分析、分子分型以及亚型生物学机制与个体化方案制定等研究工作。项目构建了OLP多中心临床队列及其生物样本库，并以此为基础进一步研究发现了OLP病情发展的多种生物标志物，这些生物标志物有望成为OLP病情监测的重要指标；利用组学数据等多模态信息，发现OLP临床转归与淋巴细胞浸润及代谢相关通路有关，如在药物应答方面，当单核细胞功能激活、NF-kappa B信号通路出现上调、花生四烯酸代谢或谷胱甘肽代谢出现增强时，羟氯喹疗的效应答则优于地塞米松；建立了基于免疫特征的OLP分子分型与预测模型；同时了发现了Th1/Th2稳态失衡、游离DNA增多以及CD8阳性组织驻留记忆性T细胞活化等可能是调控OLP发生发展的生物学机制。.项目执行期间，项目组成员发表并标注重点项目资助的SCI论文28篇；项目组获得国家级科研项目资助9项；出版教材专著8部(含英文1部)；建立国内行业标准指南7项；新授权专利2项；获四川省自然科学一等奖1项、中华口腔医学会科技奖一等奖1项；新增1名项目组成员入选中国科协青年人才托举工程。.总之，项目在科学研究、人才培养与学 科建设等方面取得了突出成绩，相关研究结果有助于形成OLP新的个性化治疗策略，降低OLP疾病负担。