miRNAs调控（稀土）Nd2O3诱导稀土尘肺的作用及机制研究

Pneumoconiosis is a kind of most serious occupational disease with the highest incidence in China. Recent years, microRNAs(miRNAs) plays an important role in a series of diseases. Studying the effect and mechanism of miRNAs on lung injury induced by rare earth dust (Nd2O3) is an important part to further clarify the pathogenesis of pneumoconiosis. Our study will screen the miRNAs with the dramatically different expression in the serum of patients with rare earth pneumoconiosis and based on the results, the related or regulated signaling pathway will be further studied. Besides that, our project is going to study the changes of miR-21 and miR-29, which are most important ones in lung inflammation and fbrosis in vitro and in vivo, and clarify the association and regulations of miR-21/ miR-29 in NF-κB/MyD88 and TGF-β/Smads signaling pathway in the lung injury induced by Nd2O3. In sum, to study the effects and the mechanisms of miRNAs in Nd2O3 induced lung injury will be helpful to explore the biomarkers for early diagnosis/prognosis pneumoconiosis disease.

尘肺病是中国职业病中发病率最高、危害最严重的一类疾病。miRNAs在很多疾病中均发挥重要的调控作用。深入研究miRNAs在稀土粉尘（Nd2O3）诱导稀土尘肺中的作用，对进一步阐明尘肺病发病机制有重要作用。本项目以稀土尘肺病人为研究对象，筛选血清中miRNAs的差异表达及其调控的信号通路。从体内和体外实验深入研究miR-21、miR-29调控Nd2O3诱导的肺部炎症及纤维化作用，阐明Nd2O3诱导的肺纤维化过程中，miR-21、miR-29二者调控NF-κB/MyD88、TGF-β/Smads信号通路中相互作用关系，探讨miRNAs 调控Nd2O3诱导肺纤维化的作用及机制，发现早期生物标记物对尘肺病早期诊断/预后进行有益探索。

1.项目背景.尘肺病是中国职业病中发病率最高、危害最严重的一类疾病。miRNAs在很多疾病中均发挥重要的调控作用。深入研究miRNAs在稀土粉尘（Nd2O3）诱导稀土尘肺中的作用，对进一步阐明尘肺病发病机制有重要作用。.2.主要研究内容.2.1筛选稀土尘肺病人血清中lncRNA、miRNAs、mRNA的差异表达及其调控的信号通路。 .2.2稀土Nd2O3粉尘致小鼠肺纤维化模型的建立，观察miR-29 在肺纤维化中的表达及意义，明确在整体动物水平调节miR-29可减轻 Nd2O3粉尘诱导的肺纤维化。 .2.3 Nd2O3粉尘致诱导细胞纤维化模型的建立及 NF-κB/MyD88、TGF-β/Smads通路指标检测，从细胞水平探miR-29 与 NF-κB/MyD88、TGF-β/Smads 信号通路之间的调控关系。.3.重要结果.3.1稀土尘肺患者血浆中共有125条lncRNA、4条miRNA、82条mRNA差异表达。 .3.2 H19通过miR-29a-3p调控TNFRSF1A的表达，进而激活NF-κB信号通路，促进Nd2O3所诱导的肺部炎症反应。.3.3 miR-29a通过TGF-β1/Smads通路抑制Nd2O3所诱导的肺纤维化的发生发展。.4.关键数据.4.1以|log2 Fold Change|≥1、P≤0.05为筛选条件，相比于对照组，稀土尘肺患者血浆中有差异表达的lncRNA 125条、miRNA 5条、mRNA 82条。.4.2过表达miR-29a能减轻Nd2O3所诱导的肺部炎症反应及纤维化。.4.3低表达 H19能减轻Nd2O3所诱导的肺部炎症反应及纤维化。.5.科学意义.阐明了 H19、miR-29a通过NF-κB、TGF-β1/Smads信号通路在Nd2O3所诱导的肺部炎症反应及纤维化中作用机制，为下一步地方性稀土所诱导的尘肺的预防和干预提供理论依据和技术支撑。