基于wnt5a介导的信号通路间crosstalk研究参芪延肾方下调肾性骨病高转换骨代谢的机制

积极治疗肾性骨病(ROD)，能降低慢性肾病(CKD)患者骨折和心血管疾病发生率，提升患者生活质量，延长生存年限。基于“肾主骨”理论从肾论治，为治疗ROD提供了重要思路。参芪延肾方是治疗CKD的有效组方，前期研究发现其改善CKD动物模型高转换ROD病理状态，降低骨组织中Wnt5a阳性表达。结合Wnt5a介导非经典Wnt通路及经典Wnt通路间crosstalk，影响成骨细胞、破骨细胞分化和功能活性的研究进展，课题组提出假说：“参芪延肾方通过干预Wnt5a介导的信号通路间crosstalk，抑制成骨细胞、破骨细胞分化和功能活性，下调ROD高转换型骨代谢。”拟采用动物模型与细胞培养，从动物-细胞-分子水平探讨参芪延肾方下调ROD高转换骨代谢的机制，并应用基因敲除、干扰和过表达等手段验证。研究将丰富“肾主骨”理论科学内涵，为临床治疗高转换ROD提供新的靶点与途径，有助于发掘治疗肾性骨病的中药新药。

Renal osteodystrophy (ROD) is independently associated with mortality and morbidity associated with fracture and cardiovascular complications in patients with chronic kidney disease (CKD). Based on the TCM theory, the traditional Chinese medicine (TCM) exhibited effects on improving bone metabolism through nourishing kidney, would be provided as a potential therapeutic method for ROD. Shenqi yanshen formula (SQYSF) ameliorate kidney injury in patients with CKD. In our previous study, SQYSF decreased the high turnover bone disease induced by different rat models with CKD, as well as Wnt5a expression. It has been reported that Wnt5a play a critical role in the differentiation of osteoblast and osteoclast and the bone function in formation and absorption. In view of this, we make the hypotheses that SQYSF depress the high turnover bone disease in CKD by inactivating the crosstalk among canonical Wnt signaling pathway and non-canonical Wnt signaling pathways, and then inhibiting the differentiation of osteoblast and osteoclast and the bone function in formation and absorption. In this study, a rat model with CKD given a special diet with high phosphorus and low calcium to further induce high turnover bone disease, and cells including bone marrow mesenchymal cell, bone marrow macrophages, osteoblast and osteoclast, will be used to explore the molecular mechanism. Moreover, osteoblast-lineage cell-specific Wnt5a-deficient mice (Wnt5a cKO), siRNA Wnt5a and Wnt5a overexpression mediated by adenovirus would be used to further prove our hypotheses. The results would be benefit to explain the TCM theory and enrich its scientific connotation, and helpful to explore potential therapeutic targets and provide promising medicine for ROD treatment.