YAP/PI3K调控超负荷应力诱导的颞下颌关节软骨退变的机制研究

颞下颌关节病是口腔医学第四大高发疾病，进展为骨关节炎时会出现明显的疼痛和功能障碍，严重影响患者的生活质量。软骨退行性变是颞下颌关节骨关节炎的主要病理改变，应力负荷过大是触发并推动其进展的重要因素，但相关病理机制尚未阐明。项目组前期研究发现，超负荷应力诱导的小鼠颞下颌关节软骨退变过程，与YAP的表达及PI3K/Akt通路有显著的相关性。超负荷应力可能改变软骨细胞内YAP活性，并联合PI3K/Akt信号通路，诱导软骨退行性变的发生。为验证该假说，本研究以YAP为效应靶点，PI3K/Akt通路为调控关键，结合体内体外实验，综合运用基因改造、活体荧光示踪、组织细胞学形态分析、基因蛋白检测等手段，探究在超负荷应力诱导的颞下颌关节软骨退变的过程中，YAP联合PI3K/Akt通路作用的分子机制。本研究将有助于深入理解超负荷应力诱导的颞下颌关节骨关节炎的发生发展过程，并为寻找相关的治疗靶点提供重要依据。

Temporomandibular Disorders are the high incidence of 4th major diseases in stomatology. The progression to temporomandibular joint-osteoarthritis (TMJ-OA) is marked by pain and dysfunction, which seriously affect the quality of life. Cartilage degeneration acts as the main pathologic change of TMJ-OA. While overloading stress is the inducer to trigger and promote this process with mechanism remains unknown. Our previous studies found that overloading stress could induce mice TMJ cartilage degeneration, which corresponded with yes-associated protein (YAP) expression change and PI3K/Akt pathway activity. Overloading stress might change the expression of YAP in chondrocytes, which further affect the activity of PI3K/Akt pathway, thus induce cartilage degeneration. To verify the hypothesis, this program takes YAP as the effective target and treats PI3K/Akt pathway the key regulator, combines with in vivo and ex vivo studies which included CRISPR/Cas9 technique, live fluorescence tracing, histomorphology analysis and various gene and protein detection techniques, and plans to explore the molecular mechanism of YAP and PI3K/Akt pathway interaction during overloading stress induced TMJ cartilage degeneration. The results will help further understand the progress of overloading induced TMJ-OA and offer the evidence for target drugs development.