BUB1在肺纤维化中的作用及其机制研究

TGF-β plays a key role in pulmonary fibrosis (PF), interfering TGF-β signal pathway could inhibit the development of PF. As a key apparatus in the TGF-β signal pathway, BUB1 plays an important role in the biological effect of TGF-β. Previous work suggested that the expression of BUB1 significantly increased during the PF, and if the expression of BUB1 in the mice fetal lung fibroblast-NIH3T3 cells was specifically down-regulated, the TGF-β induced transforming of NIH3T3 cells from lung fibroblast to myofibroblast was inhibited. Based on the previous studies, this project aim to explore the role of BUB1 in the development of PF. We will observe the effect of BUB1 on the PF in the bleomycin induced mice model, and will examine the effect of BUB1 on the TGF-β induced transforming of primary lung fibroblast and alveolar epithelial cell to myofibroblast. Finally, the further regulatory role of BUB1 in TGF-β signaling pathway will be explored in the project. In summary, this project will for the first time try to explore the crucial role of BUB1 in the development of PF, which should provide new thinking for prevention and treatment of PF, and also offer new therapeutic options for PF.

TGF-β在肺纤维化的发生发展中发挥着重要作用，干扰TGF-β信号通路能够有效抑制肺纤维化的发生发展。BUB1作为TGF-β信号转导的关键装置，对TGF-β发挥生物学活性起着关键作用。我们前期研究首次发现BUB1在肺纤维化中的表达明显升高；并且特异性干扰小鼠胎肺成纤维细胞NIH3T3细胞BUB1的表达后，TGF-β诱导其向肌成纤维细胞的分化受到抑制。鉴于以上两点，本课题拟研究BUB1在肺纤维化中的作用及机制。首先于体内观察BUB1在博来霉素诱导的肺纤维化中的作用，再在细胞水平上观察BUB1对TGF-β诱导原代肺成纤维细胞向肌成纤维细胞分化和其对TGF-β诱导肺泡上皮细胞向肌成纤维细胞转化的影响，并进一步在肺成纤维细胞中探讨BUB1调控TGF-β发挥生物学作用的机制。本课题旨在确定BUB1在肺纤维化中的作用及机制，以利于将来针对BUB1为靶点筛选和开发治疗肺纤维化的药物。

肺纤维化是严重危害健康的呼吸系统常见并发症，是各种不同病因的肺间质疾病的最后共同结局。大量研究表明，干扰TGF-β信号通路能够有效抑制肺纤维化的发生发展，BUB1作为TGF-β信号转导的关键装置，对TGF-β生物学活性的发挥起着关键作用，目前，BUB1在纤维化疾病中的作用还未见报道。本课题深入研究了BUB1在肺纤维化中的作用及其机制。本课题研究成果首次证实：（1）BUB1在肺纤维化的发生发展中具有重要作用，特异性抑制BUB1的活性能够显著减轻博来霉素诱导的小鼠肺纤维化；（2）特异性抑制BUB1的活性或沉默BUB1基因的表达均能够抑制TGF-β诱导肺成纤维细胞向肌成纤维细胞分化的作用和TGF-β诱导肺上皮细胞通过EMT向肌成纤维细胞转化的作用；（3）特异性抑制BUB1的活性或沉默BUB1基因的表达均能够抑制TGF-β依赖性的细胞内Smad信号转导通路和non-Smad信号转导通路。上述研究证实了BUB1在促进肺纤维化发生发展中的重要作用，并明确BUB1能够作为肺纤维化药物治疗的新靶点。