Bmi1信号组成性激活诱导肺脏上皮干细胞衰竭在小鼠矽肺病理发生中的作用与机制研究

肺脏远端支气管肺泡干细胞(BASC)和肺泡II型祖细胞(ATP)是维持肺脏损伤修复和稳态的主要干细胞来源，但它们之间的干细胞层次和在矽肺发生中的分子机制不清；淋巴瘤Mo-MLV插入区1同源物(Bmi1)和Wnt/β-catenin是调控干细胞自我复制和增殖的关键因子。我们前期发现小鼠肺脏上皮细胞Bmi1信号随着矽肺病理进程逐渐增强，提示组成性激活Bmi1通过与Wnt/β-catenin信号相互作用导致上皮干细胞衰竭参与矽肺病理发生。本项目拟探讨(1)BASC和ATP亚群细胞组成的异质性和基因表达谱差异；(2) Bmi1细胞在矽肺病理发生过程中的细胞谱系；（3）Bmi1基因缺失对肺脏上皮干细胞在矽肺病理发生中的增殖与分化影响；（4）Bmi1和Wnt/β-catenin相互作用对肺脏上皮干细胞增殖与分化的作用与机制等内容，为研究肺脏上皮干细胞在矽肺病理发生中的作用与分子机制提供新的的思路。

Both of the bronchoalveolar stem cells (BASC) and alveolar type II progenitor cells (ATP) are indispensible source of stem cells for injury repair and maintenance of tissue and function homeostasis in distal lungs. However the hierarchical relation and underlying regulatory mechanism between them and their roles in the pathogenesis of silicosis remain exclusive. The lymphoma Mo-MLV insertion region 1 homolog (Bmi1) and Wnt/β-catenin signaling both are pivotal factors regulating the self-renewal and proliferation of adult stem cells. We previously found that a gradually enhanced Bmi1 signaling in the epithelial cells of mouse silicosis lung along with the pathogenic progression, suggesting that the constitutive activation of Bmi1 has an impact on the pathogenesis of silicosis through a mechanism by which it interacts with the Wnt/β-catenin signaling to induce a proliferative exhaustion of epithelial stem cells. Therefore, the present proposal is attempt to investigate: (1) the differential expression profile and heterogeneity between BASC and ATP cell populations in mouse lung; (2) the differential cell lineage tracings of Bmi1 expressing epithelial cells during the pathogenesis of silicosis in mice; (3) the impact of Bmi1 deficiency on the proliferation and differentiation of lung epithelial stem cells during the development tof silicosis in mice; and (4) the role and underlying mechanism of the interaction between Bmi1 and Wnt/β-catenin signaling in the proliferation and differentiation of lung epithelial stem cells during the pathogenic progression of silicosis in mice. An accomplishment of this proposal will allow us to better understand the role and molecular mechanisms of lung epithelial stem cells in injury repair and pathogenesis of silicosis in particularly, and other chronic lung diseases in general, which may also provide novel clues for studies in lung epithelial stem cells.