lncRNA-H19/miR-29b-3p/BBC3通路调控矽肺纤维化的机制研究

矽肺是吸入含SiO2粉尘引起以肺纤维化为特征的的严重呼吸病，尚无特效治疗措施，其主因在于矽肺纤维化的发病机制还未明确，缺乏针对性干预治疗的靶点。长链非编码RNA(LncRNA)可通过ceRNA等多种机制调控下游蛋白表达。申请者前期研究发现，凋亡蛋白BBC3(PUMA)参与了矽肺纤维化的发生发展；miRNA高通量筛选发现miRNA-29b-3p参与下调BBC3；LncRNA高通量筛选提示lncRNA-H19具有与miRNA-29b-3p的潜在结合位点；生物信息学分析提示BBC3是受lncRNA-H19调控的宿主基因。据此，申请者提出“lncRNA-H19/miRNA-29b-3p/BBC3通路是矽肺纤维化诊治的有效和关键靶点”假说，拟应用分子生物学和经典药理学方法，从整体、细胞和分子水平系统阐明此通路在矽肺纤维化中的功能和作用机制，为寻找临床干预治疗矽肺纤维化的靶点提供新思路和实验依据。

The inhalation of silicon dioxide particles leads to silicosis, an untreatable respiratory disease characterized by progressive pulmonary fibrosis. Because of the highest morbidity, disability and mortality rate, the harmfulness of silicosis occupied the first place among pneumoconiosis in China. Although substantial and increasing studies were undertaken to dissect the pathological mechanisms underlying the process of pulmonary fibrosis induced by silica, the primary cause of this devastating pathophysiological process remains elusive. On the other hand, although comprehensive management strategies help to improve quality of life and slow deterioration, there is no targeted curative treatment exists. Thus, further efforts are needed to find new target to control the fibrosis induced by silica. Recent literature have described the presence of long noncoding RNA (lncRNA) in different physiological and pathological process. Because of the specific space structure, lncRNA could modulat the expression of numerous downstream protein via different mechanisms, such as competing endogenous RNA (ceRNA), in which, lncRNA act as sponges for small RNA. Our previous studies suggested that BBC3/PUMA, an important member of apoptosis protein family, play a key role in fibroblast proliferation and migration induced by silica, following acceleration of pulmonary fibrosis. However, the detailed cellular and molecular mechanisms of BBC3/PUMA underlying the pulmonary fibrosis triggered by silica remain unknown. LncRNA microarray assay suggested that lncRNA-H19 expression in peripheral plasma from patients of silicosis was increased compared that of healthy donor. Bioinformatics analysis indicate lncRNA-H19 is the regulator of BBC3/PUMA. Furthermore, microRNA microarray assay found that miR-29, which can be regulated by LncRNA-H19, was also decreased. Interestingly, miR-29 can also inhibit the expression of BBC3/PUMA. Based upon our previous study and primary data from our lab, we hypothesized that lncRNA-H19/miR-29/BBC3 pathway will be the potential target of curative treatment for pulmonary fibrosis induced by silica. The proposed study will be initiated in human sample followed by study in intact animals as well as primary cell cultures. Studies using classic pharmacological methods will be combined with molecular biological techniques as well as immunological methods. Our study will decipher the link between lncRNA-H19/miR-29/BBC3 pathway and pulmonary fibrosis induced by silica, providing a novel potential target from lncRNA to open up novel therapeutic avenues for silicosis.