Wnt10a通过抑制mTOR信号诱导自噬调控骨衰老的机制研究

骨衰老是导致骨质疏松、颌骨缺损和牙槽嵴重度吸收等疾病的重要因素，严重危害口腔功能和全身健康。骨衰老的影响因素复杂，mTOR信号调控的自噬可能参与延缓骨衰老的过程。申请人前期发现WNT10A失功能突变患者有早发型骨密度降低和增龄性骨流失的骨早衰表型，成功构建了复制患者骨衰老的Wnt10a敲除小鼠EIIa-Cre;Wnt10afl/fl并进行初步研究，提出科学假设“Wnt10a抑制mTOR，诱导细胞自噬，延缓骨衰老”。本项目拟利用该小鼠模型，观察不同年龄段的骨发育和增龄性骨质骨量变化，明确Wnt10a在骨衰老中的表达模式及延缓骨衰老的作用；利用小鼠模型和WNT10A突变患者颌骨骨髓间充质细胞，以RNA-seq和表型逆转实验，验证Wnt10a-mTOR-自噬在延缓骨衰老中的机制。本项目为阐明骨衰老的分子机制提供新视角，对于精准防控增龄性骨流失，延缓或防止老龄化相关的骨质疏松等疾病具有积极意义。

Bone aging plays an important role in diseases such as osteoporosis, jaw defect and severe alveolar bone resorption, which seriously damages the patients’ oral function and general health. Autophagy regulated by mTOR signaling might act as one of the complex biological processes against body aging. In our preliminary research, we found that patients with WNT10A loss-of-function variants had the phenotype of premature bone aging, including reduced bone density at young age and age-related bone loss. We further created the Wnt10a knockout mouse and observed the bone aging phenotype similar to human patients. Therefore, we hypothesize that Wnt10a slows bone aging by inducing cell autophagy via inhibiting mTOR signaling. In this study, we will employ mouse model to observe bone development and age-related bone quality in different age groups, and then to explore the expression pattern of Wnt10a in bone aging process and its specific role in delaying bone aging. Secondly, we will use mouse model and culture mesenchymal cells of jaw bone marrow from the patient with Wnt10A mutation. RNA-seq and rescue experiment will then be employed to verify the mechanism of Wnt10a-mTOR-autophagy axis in delaying bone aging. This study findings will provide new perspectives to help us understand the molecular mechanism of bone aging, which is of great significance to precisely control age-related bone loss and prevent health problems in aging population such as osteoporosis.