过大应力负荷是TMJOA的关键致病因素之一，但其力学信号转导通路及分子调控机制尚不明确。本项目前期研究表明过大应力负荷可激活软骨细胞YAP形成YAP/TEAD1转录调控复合物，调控HTRA1表达，诱发TMJOA病理进程；软骨细胞RAP2能够直接响应力学刺激，调控Hippo/Yap活性。结合国内外最新研究，本项目以Rap2/Hippo/Yap力学信号转导通路为切入点，拟深入探究过大应力负荷诱发TMJOA的分子机制。本项目拟采用多种基因小鼠进行体内、体外研究，明确Rap2/Hippo/Yap通路在过大应力负荷诱发TMJOA中的作用；再通过ATAC-seq、bioChIP-seq等技术阐明YAP调控HTRA1转录活性的分子机制；最后利用基因敲除、RNAi技术及小分子药物探讨靶向抑制YAP干预TMJOA病理进程的可行性。本项目有望进一步阐明TMJOA的发病机制，为其治疗提供理论依据与数据支持。

The excessive mechanical stress is a crucial factor in initiating temporomandibular joint osteoarthritis (TMJOA) pathological process. However, the mechanotransduction pathway and its molecular mechanisms are still unknown. Our previous studies demonstrated that the excessive mechanical stress would induce the activation of YAP in chondrocytes, which could translocate into nucleus and bind to TEAD1 to generate the transcript regulation complex YAP/TEAD1. Then YAP/TEAD1 would trigger the HTRA1-DDR2-MMP13 axis and lead to the onset of TMJOA. Besides, RAP2 could respond to mechanical stimulation directly and contribute to regulating the activity of YAP in chondrocytes via HIPPO pathway. Based on the latest researches and our preliminary data, we propose to focus on the Rap2/Hippo/Yap mechanotransduction pathway to further explore the molecular mechanisms of TMJOA pathological process induced by the excessive mechanical stress. First, we will confirm the roles of Rap2/Hippo/Yap pathway in the development of TMJOA under excessive mechanical stress in vivo and in vitro by various transgenic mice. Second, we will investigate the molecular mechanisms of YAP in regulating the transcription of HTRA1 via ATAC-seq and bioChIP-seq analyses. And finally, we will explore the feasibility of YAP targeted inhibition to block the pathological process of TMJOA through the conditional gene knockout mice model, RNAi interference, and small molecule drug. This project will elucidate the molecular mechanisms in regulating TMJOA pathological process under excessive mechanical stress, and provide novel supporting information for the new methods of TMJOA treatment.