circHECTD1调控miR-22-3p介导的巨噬细胞焦亡在石英致肺纤维化中的作用机制研究

矽肺是以肺组织持续慢性炎症和进行性纤维化为特征的职业病，发病机制尚未明确。新近研究显示细胞焦亡在纤维化疾病中介导形成“焦亡-炎性反应-纤维化”轴样病理改变。课题组前期发现石英刺激巨噬细胞后差异表达的circHECTD1、miR-22-3p可能参与调控细胞焦亡。本题拟建立circHECTD1/miR-22-3p沉默和/或过表达的巨噬细胞和小鼠矽肺模型，体外实验利用RNA-FISH、RNA pull-down、siRNA干扰等手段，探讨circHECTD1调控miR-22-3p介导的巨噬细胞焦亡在矽肺纤维化的机制；体内实验分析不同染尘时间小鼠肺组织病理改变、巨噬细胞焦亡和肺功能的关系，阐明circHECTD1调控miR-22-3p介导巨噬细胞焦亡在石英致肺纤维化的作用规律；并探究hucMSC-Exos通过抑制细胞焦亡拮抗矽肺纤维化的可能机制。为矽肺发病机制研究提供新线索，为矽肺防治提供新思路。

Silicosis, a severe occupational disease, is characterized by persistent chronic inflammation and progressive pulmonary fibrosis, but the pathogenesis is unclear. Recent studies have shown that cell pyroptosis promotes the formation of "pyroptosis-inflammation-fibrosis" axis-like pathological changes in fibrotic diseases. We have formerly found that the differentially expressed circHECTD1 and miR-22-3p in macrophages stimulated by silica may be involved in the regulation of macrophage pyroptosis. In this project, we will employ circHECTD1/miR-22-3p silenced and/or overexpressed macrophage model and mouse silicosis model, respectively. In vitro experiment, RNA-FISH, RNA pull-down and siRNA interference measures are utilized to explore the mechanism of circHECTD1 regulating miR-22-3p-mediated macrophage pyroptosis in silicosis fibrosis. In vivo experiment, we will analyze the relationship among lung pathological changes, macrophage pyroptosis and lung function in mice with different silica-exposed time to clarify the rule of macrophage pyroptosis mediated by circHECTD1-regulated miR-22-3p in silica-induced pulmonary fibrosis. Furthermore, we will explore the possibility of hucMSC-Exos antagonizing silicosis fibrosis by inhibiting pyroptosis. This project may provide new clues for the research of the pathogenesis of silicosis and shine a light on the prevention and treatment of silicosis.