巨噬细胞中的Fcgr3在矽肺进展过程中的功能及机制研究

矽肺病是一种因长期吸入游离二氧化硅粉尘所引起的肺尘埃沉着病。截至目前，国内外均没有针对矽肺特效的治疗药物。因此，探究矽肺潜在的干预靶点及其作用机理对于矽肺的防治具有重要的意义。本课题组前期通过人群队列研究发现血清中的IgG水平在矽肺人群中显著升高。IgG的低亲和力受体基因FCGR2A在矽肺病人的肺组织中显著升高，其在小鼠中的同源基因Fcgr3也在矽肺中显著升高。全身敲除小鼠Fcgr3能够显著延缓矽肺中的炎症和纤维化进展。单细胞转录组学显示，Fcgr3高表达在巨噬细胞。为了进一步明确Fcgr3在矽肺进展中的功能，并从中探寻矽肺可能的干预靶点，我们拟进行如下研究：（1）条件性敲除小鼠巨噬细胞中的Fcgr3，造模并观察其对矽肺进展的影响；（2）多组学分析结合实验技术，从分子水平探究小鼠巨噬细胞中Fcgr3下游的关键信号通路。这些研究将有助于我们进一步理解矽肺的发病机制，并从中探索有效的干预靶点。

Silicosis is a kind of pneumoconiosis caused by long-term inhalation of silica dust. Up to now, there are no effective therapeutic drugs for silicosis worldwide. Therefore, it is of great significance to explore the potential therapeutic targets as well as their mechanisms in silicosis. In a previous cohort study, we found that the serum IgG level was significantly increased in silicosis population. FCGR2A, a gene encoding one low affinity receptor of IgG, was significantly increased in the lung tissues of silicosis patients, and its homologous gene in mice (Fcgr3) was also significantly enhanced in mice silicosis lungs. The Fcgr3 knockout mice showed significant attenuation of inflammation and fibrosis in the progression of silicosis. Results from single-cell transcriptomics showed that Fcgr3 was highly expressed in pulmonary macrophages in silicosis. In order to further clarify the function of Fcgr3 in the progression of silicosis and explore the possible therapeutic targets of silicosis, we plan to carry out the following studies: (1) conditionally knock out Fcgr3 in mouse macrophages to establish silicosis models and observe its effect on the progression of silicosis; (2) explore the key downstream signaling pathways of Fcgr3 in mouse macrophages from the molecular level. These studies will help us to further understand the pathogenesis of silicosis, and have important theoretical significance for exploring effective intervention targets.