PARD6A介导细胞极性改变激活YAP促进OSF形成的机制研究

血管内皮细胞间质转化（EndMT）和成纤维细胞被激活在口腔粘膜下纤维性变（OSF）发病机制中发挥关键作用。申请人2019年在JDR上发表研究证实，YAP是OSF组织中诱导EndMT的关键分子，近期还发现OSF组织中极性蛋白PARD6A高表达，且体外能活化YAP，提示PARD6A介导细胞极性改变激活YAP促进OSF形成。本项目将分别以血管内皮细胞和成纤维细胞为研究模型，检测极性蛋白PARD6A对血管内皮细胞EndMT和成纤维细胞胶原代谢的影响，并通过动物实验和OSF组织样本进行验证；同时体外实验分析PARD6A、YAP和候选蛋白的互作关系、miR-134-3p对PARD6A的调控作用，以期揭示PARD6A介导血管内皮细胞和成纤维细胞极性改变活化YAP的内在分子机制，及PARD6A使OSF炎性微环境中成纤维细胞再极化后激活的分子机制。本研究将有助于阐明OSF病理机制，筛查敏感人群和寻找治疗靶点

The endothelial-mesenchymal transformation (EndMT) of vascular endothelial cells and the activation of fibroblasts play an important role in the pathogenesis of oral submucosal fibrosis (OSF). In our previous study, we demonstrated that YAP was a key molecule to induce EndMT, which published in JDR in 2019. Our recent research also found that the polar protein PARD6A, highly expressed in OSF tissue, could activate YAP. It is suggested that cell polarity change mediated by PARD6A would activate YAP to promotes OSF formation. In this project, the vascular endothelial cells will be used as research models to detect the effect of polar protein PARD6A on EndMT via YAP, and the fibroblasts used as research models on collagen metabolism. And the observation will be confirmed by the researches in animal and OSF tissue specimens. Furthermore, the interaction among PARD6A, YAP and candidate proteins, and the regulatory effect of mir-134-3p on PARD3A will be analyzed in vitro. The aim of this study is to reveal the molecular mechanism of PARD6A-mediated polar change activating YAP in vascular endothelial cells and fibroblasts, and the activation of fibroblasts after repolarization in OSF inflammatory microenvironment by PARD6A. This project will help elucidate the pathological mechanism of OSF, screen sensitive populations and find therapeutic targets.