非编码RNA在大气细颗粒物致气道炎症反应中的作用机制研究

Inflammation is an important reason of lung diseases induced by airborne fine particulate matters, and it is of great significance to elucidate its inflammatory mechanism. Non-coding RNAs, as a new field of epigenetics, are used to explore the mechanisms of diseases. Our team has been studying the mechanisms of non-coding RNAs in the toxicity of environmental chemicals for about ten years. And we firstly reported the pathogenic mechanisms of non-coding RNAs, including miRNAs, lncRNAs and circRNAs in toxicology around the world. We found that non-coding RNAs were correlated with PM2.5 toxicity. This project aims to investigate the correlation between non-coding RNAs and key inflammation-related signal molecular pathways, and systematically elucidate the mechanisms of non-coding RNAs and their regulation network on the airway inflammation caused by PM2.5, based on network-based muti-omics analysis and other new techniques of molecular biology. The inflammation models of human airway epithelial cells and animals will be constructed based on the actual exposure dose of PM2.5 in mankind. Meanwhile, population-based study on the PM2.5 exposure will be carried out. Our team consists of three senior professors and other brilliant researchers, with deep roots in their fields of molecular toxicology, environmental chemistry or environmental epidemiology. We will cooperate with each other to reveal the mechanisms of non-coding RNAs in PM2.5-induced health hazards. This will contribute to the realization of the objective of the major research plan.

炎症是大气细颗粒物引起多种肺部疾患重要因素，阐明其致炎机制是有效预防和治疗的基础。非编码RNA是从表观遗传学视野探索疾病机制，我们过去十年围绕环境化学物对非编码RNA影响及其机制开展系列研究，率先在国际毒理学领域报道了miRNA、lncRNA及circRNA等非编码RNA在毒效应机制中作用，并发现若干非编码RNA与PM2.5毒作用的联系。基于此，本项目模拟人群实际暴露PM2.5剂量，构建人气道上皮细胞及动物气道炎症模型，结合暴露人群研究，基于网络调控多组学分析等新颖方法及分子生物学新技术，筛选和鉴定PM2.5致炎中有重要功能的非编码RNA及其调控网络，探析它们与细胞关键炎症信号通路的关联，系统阐明非编码RNA及其调控网络在PM2.5致气道炎症中机制。本项目汇集基础雄厚的分子毒理、环境化学、环境流行病团队，协同研究以揭示PM2.5健康危害的非编码RNA机制，助推重大研究计划总目标实现。

本项目构建了PM2.5和其模拟颗粒物致细胞和动物炎症反应的评价模型，明确了多个非编码RNA在PM2.5和其模拟颗粒物致炎症反应的功能，PM2.5或模拟细颗粒物可引起circRNA、lncRNA、miRNA等非编码RNA的差异表达。其中lncRNA LINC00341和LOC101927514等分别在PM2.5诱导的细胞周期阻滞和细胞炎性反应中发挥重要作用，lnc-PCK1-2:1是与PM2.5中Pb毒性组分相关的lncRNA，能够抑制PM2.5模拟物诱导的细胞炎性反应。项目开创性地开展了circRNA在PM2.5诱导细胞炎性反应中调控功能的相关研究，第一次构建了circRNA、lncRNA和miRNA调控PM2.5诱导炎症反应的网络互作关系，首次揭示了circRNA互作蛋白抑制PM2.5诱导炎症反应的分子机制。首次研究了circNOL10与转录因子SCML1结合抑制细胞毒性的功能，和参与基因转录调控在细胞毒性中的分子机制。本项目阐明了非编码RNA对PM2.5致炎症反应中NF-κB、STAT3和MAPK等炎症信号通路激活的调控形式。人群血浆检测结果表明，lnc-MTRNR2L12-3:6的表达量与PM2.5的暴露量和IL-6的含量呈负相关，lnc-GPR39-7:2的表达量与PM2.5的暴露量和TNF-α的含量呈负相关，这两个lncRNAs具有作为大气PM2.5短期暴露致机体炎症反应早期标志物的潜力。项目的研究结果为非编码RNA在呼吸系统疾病的作用机制研究提供了更多新的证据。. 本项目多项研究发现被编入《分子毒理学》和《毒理学基础》等教材，取得的研究成果已发表标注项目号的SCI论文24篇，中文5篇，已培养5名博士生和9名硕士生。项目负责人蒋义国于2019年获得“中国毒理学杰出贡献奖”，及以第一完成人获国家教育部高校科研成果二等奖和广东省科技成果二等奖。