粘蛋白Muc1在肺纤维化发病中的调节作用和细胞分子机制研究

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with unknown etiology and few treatment options. Hence, identifying the mechanism that promote this disease is urgently needed to develop novel therapeutics. Our team for the first time found that Mucin 1 (Muc1), an important regulatory protein, can adjust the bacteria, viruses, and tobacco smoke-induced inflammatory response. Our recent preliminary studies demonstrated that it was highly expressed in the lung following bleomycin challenge and that Muc1-/- mice displayed an attenuated pulmonary fibrosis，with an improved lung function. Based on our previous and preliminary studies, we would adopt a WT and Muc1-/- mouse model of pulmonary fibrosis and apply histopathological and molecular biological techniques, combining with in vivo and in vitro experiments, to investigate the effect and the mechanisms of Muc1 on the epithelial injury, fibroblasts activation and pro-fibrotic epithelial cell-fibroblast interactions. This project will determine Muc1 promotes IPF in vivo and in vitro. Successful completion of these studies will help improving the understanding of underlying mechanism of this disease. This could yield novel therapeutic targets for the.patients with chronic fibrotic lung disease, as well as open up a novel research field in the pathogenesis and treatment of pulmonary fibrosis.

特发性肺纤维化（IPF）是一种病因不明、进展迅速、致死率极高的间质性肺疾病，缺乏有效治疗方法。因此，阐明肺纤维化的病理机制对寻找有效治疗方法具有重要意义。我们课题组首次发现粘蛋白Muc1是一种重要的炎症调节蛋白，能够调节细菌、病毒和烟草烟雾所诱导的炎症反应。我们近期初步研究发现，在博来霉素诱导的肺纤维化小鼠模型肺组织中Muc1呈现高表达，且Muc1基因敲除（Muc1-/-）能够改善肺纤维化小鼠的肺功能，减轻博来霉素诱发的肺纤维化。本项目将在前期研究成果的基础上，应用Muc1-/-和野生型小鼠建立肺纤维化小鼠疾病模型，结合体外细胞培养技术，应用组织病理学、细胞分子生物学等实验手段，研究Muc1对肺纤维化损伤修复过程中上皮细胞损伤和上皮间质转化、成纤维细胞活化以及上皮细胞—成纤维细胞交互作用的影响及机制。本研究将加深对IPF发病机制的新认识，并可能揭示新型有效诊治靶点。

本项目通过收集IPF患者和博来霉素诱导的肺纤维化小鼠的肺组织，检测到Muc1在IPF患者和博来霉素诱导的肺纤维化小鼠肺组织中均呈现显著的高表达。进一步的机制研究发现，在博来霉素诱导的肺纤维化发病过程中，上调表达的Muc1可能通过调控TGF-β1信号通路，进而影响肺泡上皮细胞损伤和EMT、成纤维细胞活化以及巨噬细胞的极化，最终引起肺纤维化。在研究中我们还意外发现，博来霉素诱导的肺纤维化小鼠肺组织中Muc1呈现高表达、骨形成蛋BMP4呈现显著低表达，且两者之间可以相互作用，共同影响肺纤维的发生发展。因此，我们也构建了BMP4+/-小鼠，发现在博来霉素诱导的肺纤维化发病过程中，表达下调的BMP4一方面可以通过调控TGF-β1信号通路，抑制成纤维细胞衰老，进而抑制成纤维细胞活化；另一方面还可抑制TGF-β1诱导肺上皮细胞EMT和衰老；最终减轻肺纤维化。通过本项目研究加深了对肺纤维化发病机制的新认识，并为进一步开发治疗肺纤维化新型高效药物奠定研究基础，推动肺纤维化新型药物的研发，将造福更多的肺纤维化患者。