Hippo信号调控肺上皮细胞衰老和重塑参与特发性肺纤维化发病的机制研究

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous and lethal age-related disease, which seriously affects the quality of life and life cycle of elderly patients. A growing body of evidence supports that drift of development and regeneration signals in epithelium drives IPF. The development pathway, Hippo, is a recently identified signaling cascade which regulates lung morphogenesis and homeostasis. Our preliminary study shows that Hippo signal is abnormal activation in alveolar epithelial cells of IPF patients and differentially expressed genes are enriched in remodeling and senescence markers of epithelium. We speculate that the Hippo signal initiates IPF occurrence and development through ① modulating plasticity of epithelium by transcriptional control SOX2, SMAD3 target genes and crosstalk Wnt/β-catenin classic signal; ② mediating ageing of epithelium by regulation of cell senescence and senescence associated secretory phenotype. This project intends to clarify the mechanism of Hippo in aging and remodeling process of epithelium in IPF, clear the core molecular of Hippo and signal interaction network in the pathogenesis of IPF through multiple levels of the crowd, animal model, cell model, by optimized AAV carrier technology. This project will select new targets and propose new strategies for the diagnosis and treatment of IPF.

特发性肺纤维化（IPF）是异质性的、致死性的老化相关疾病，严重影响老年患者生活质量和生命周期。研究发现肺上皮细胞发育再生信号漂移参与启动IPF发生发展。发育信号Hippo是调控肺脏形态发生和组织稳态等病生过程的新兴信号。本项目前期研究发现，Hippo信号在IPF患者肺上皮细胞异常激活，差异表达基因功能富集于上皮细胞重塑和衰老标志物。我们推测Hippo信号①转录调节SOX2、SMAD3等靶基因、串联Wnt/β-catenin等经典信号调控肺上皮细胞重塑；②调节细胞衰老及衰老相关分泌表型介导肺上皮细胞老化；从而参与肺上皮细胞启动IPF发生发展。本项目拟通过人群、动物模型、细胞模型等多个层面，利用优化的AAV载体等技术，阐明Hippo在IPF肺上皮细胞重塑和衰老中的作用和机制；明确IPF发病过程中Hippo信号发挥重要作用的核心分子和互作信号网络；遴选IPF诊疗的新靶点，提出IPF治疗新策略。

特发性肺纤维化（IPF）是异质性的、致死性的老化相关疾病，是肺癌的独立预后指标，严重影响老年患者生活质量和生命周期。发育信号Hippo是调控肺脏形态发生、组织稳态、免疫反应等病生过程的新兴信号。本项目首先成功构建博来霉素（BML）诱导的肺纤维化小鼠模型和对肺泡上皮细胞有亲嗜性的AAV2/9载体，通过气道内注射给药，干预靶基因表达。通过生物信息学分析、人群、动物模型、细胞模型等多个层面，发现：① Hippo信号在IPF患者肺上皮细胞异常激活，差异表达基因功能富集于肺泡上皮细胞重塑和衰老标志物，其中包括衰老相关分泌表型（SASP）炎症因子互作信号；② BLM诱导的小鼠模型肺纤维化严重程度与肺泡上皮细胞衰老相关，Hippo信号关键转录共激活因子YAP调节肺泡上皮细胞衰老，参与BML诱导的小鼠肺纤维化发生发展；③ 进一步遴选出新的差异表达的炎症因子IL-19，其通过与Hippo信号互作的TGF-1β/Smad信号激活肺成纤维细胞促进肺纤维化；④此外，Hippo信号YAP通过PTEN/AKT/mTOR信号介导自噬，调控肺腺癌细胞增殖，同时，YAP类似物TAZ转录上调AREG，激活EGFR信号，促进肺腺癌血管生成，提高EGFR-TKI吉非替尼的敏感性。