OPN激活FAK/Src/YAP轴参与支气管哮喘气道重塑的机制研究

气道重塑是哮喘的重要特征之一，与哮喘患者气流不可逆性受限以及病情严重程度相关。研究认为，气道平滑肌细胞增殖和迁移在气道重塑过程中发挥重要作用。我们前期研究表明，哮喘时OPN水平上调，诱导YAP表达及活化，且两者均参与促进气道平滑肌细胞的增殖和迁移，但YAP是否介导OPN促细胞增殖和迁移的作用，及其上下游信号通路尚不清楚。本研究在此基础上，拟探讨OPN是否通过与其受体整合素αvβ3结合，激活FAK/Src信号通路，诱导YAP表达及活化，上调THBS1，促进气道平滑肌细胞增殖和迁移；阐明YAP下游靶基因THBS1是否可进一步诱导FAK磷酸化，形成FAK/YAP-THBS1正反馈环路；揭示特异性干预FAK/Src/YAP轴是否可抑制气道平滑肌细胞增殖和迁移，缓解动物模型气道重塑严重程度。本项目将从大鼠原代气道平滑肌细胞和慢性哮喘模型两个方面验证我们的研究假设，为哮喘气道重塑的靶向治疗提供依据。

Airway remodeling is a main feature of asthma and is closely related to the progression of irreversible airflow limitation and the severity of asthma. Airway smooth muscle cell (ASMC) proliferation and migration are believed to play a critical role in the progression of airway remodeling. Our previous studies found that OPN was augmented in serum and bronchoalveolar lavage fluid of chronic asthma rat model, and induced YAP expression and activation. OPN and YAP were both related to the ASMC proliferation and migration. However, whether YAP mediates OPN-induced cell proliferation and migration and the upstream and downstream regulatory mechanisms of YAP remain to be elucidated. Herein, we will further explore: Whether OPN induces YAP expression and activation, upregulates THBS1 expression, stimulates ASMC proliferation and migration by binding to integrin αvβ3 and modulating FAK/Src pathway; Whether THBS1, a downstream target gene of YAP, induces FAK phosphorylation and then forms a positive feedback loop; Whether specific intervention of FAK/Src/YAP axis inhibits proliferation and migration of ASMC and development of airway remodeling. This study will further validate our hypothesis by primary cultured airway smooth muscle cell and animal models of asthma. The development of this study will provide the direct evidence for the targeted therapies of airway remodeling in asthma.