OR1A2在口腔扁平苔藓发生发展中的作用及潜在临床意义

The pathogenesis of oral lichen planus (OLP) generally agreed is that Toll-like receptors(TLRs) on antigen-presenting cells recognise putative triggers such as microorgnism and activate T cell, then the production of Th1 cytokines is increased and basal keratinobyte apoptosis is induced. Clarifying the role of key genes and their encoded proteins during that couse is most important (Immunity 2015). Previous research has revealed that OR1A2 was expressed highly in the OLP tissue and TLR4 appeared with the trend of high and low. So the hypothesis was presented that OR1A2 played a role in the development of OLP through affecting the TLRs-related immune response which might be relatede to Candida albicans. To confirm that, firstly the expression level of OR1A2 will be tested in multiple-center and large-sample OLP cohort to verify the the high expression of OR1A2 in OLP and explore its correlation to disease severity and susceptibility. Secondly, the interactions between OR1A2 and TLRs will be investigated to clarify the action mechanism of OR1A2 in OLP and the clinical application value. Thirdly, the cause of high expression of OR1A2 will be explored by investigating the impact of Candida albicans on OR1A2. That can not only clarify the role and mechanism of OR1A2 in the devolopment of OLP and the possibility of acting as a new target to prevent and treat OLP, at the same time, but also to clarify its possible role in immune-mediated chronic inflammatory diseases.

抗原提呈细胞表面Toll样受体(TLRs)被微生物等触发，导致T淋巴细胞活化，引起上皮细胞凋亡是口腔扁平苔藓(OLP)关键的发病机制，阐明关键基因及其编码蛋白在其中的作用为学科前沿(Immunity2015)。课题组前期发现OR1A2在OLP组织高表达且与TLR4呈同高同低趋势，结合申请人既往OLP免疫机制及与白色念珠菌(Cal)关系的研究，我们假定OR1A2可通过影响TLRs介导免疫应答，参与OLP发生，且与Cal刺激有关。为证实此假说，拟①在多中心大样本OLP队列中验证OR1A2高表达及其与病情严重度的关系；②通过考察OR1A2与TLRs的交互作用，研究其作用机制及应用价值；③通过考察Cal对OR1A2的影响，探索OR1A2高表达的可能原因。成果不仅可阐明OR1A2在OLP中的可能机制及其作为OLP防治新靶标的可能性，同时还为阐明该新分子在免疫介导慢性炎性疾病中的可能作用奠定基础。

口腔扁平苔藓(OLP)是一种病因不明、慢性迁延且存在癌变倾向的常见免疫相关性口腔黏膜疾病，其病因和发病机制的研究一直为热点领域。通过组织学染色，我们发现OR1A2在OLP患者上皮下病损组织中呈高表达，且部分样本上皮细胞出现阳性信号；成功构建了正常口腔黏膜上皮细胞及异常增殖细胞OR1A2基因过表达稳转株：过表达后，细胞增殖能力显著提升，侵袭能力减弱，迁移能力增加，外泌体成分明显改变。同时，通过单细胞转录组联合免疫组库测序构建OLP患者口腔病损免疫微环境图谱：发现OLP患者的大多数T细胞具有干扰素反应特征，并找到患者共享的CDR3序列；通过单细胞测序和空间转录组学描绘口腔扁平苔藓中CD8+组织驻留记忆性T细胞的分布，发现不同临床类型OLP中CD8+TRM及其细胞产物在空间分布中具有明显差异；通过文献计量学方法发现近期研究热点集中在OLP的癌变和疾病管理，对OLP诊断标准进行了中国化发展，并提出活检适应证的“23原则”；探索了针对OLP的不同临床治疗手段，发现光动力疗法和外用钙调磷酸酶抑制剂对OLP均有显著疗效。执行期间已发表标注项目资助的论文25篇，其中SCI论文18篇，中文核心7篇；项目负责人获得国家自然科学基金区域创新发展联合基金重点支持项目和中国医学科学院临床与转化医学研究基金重点培育项目；授权发明专利2项；主编出版论著《案析口腔黏膜病学》（第2版）、《Case Based Oral Mucosal Diseases》，副主编出版国家卫生健康委员会“十三五”规划教材《口腔黏膜病学》（第5版）；1名项目组成员入选国家高层次引进人才青年计划，1名项目组成员晋升正高，1名晋升副高，培养博士生8名，硕士生15名；项目负责人于2018年荣获中华口腔医学会科技奖一等奖，2020年9月被评为“第十四批四川省卫生健康委员会学术技术带头人”。通过本项目的实施，更深入地了解了OLP发生发展的过程，为OLP的分子诊断和个性化治疗提供了新的见解。