GRP78/Bip信号通路在假体周围骨溶解病情进展中的作用及其机制研究

GRP78/Bip参与体内绝大多数应激反应，可从细胞内转至细胞外。目前关于GRP78/Bip靶向治疗的研究存在分歧，其治疗作用和机制尚无合理解释。前期预实验发现，GRP78/Bip能同时在细胞内和细胞外持续高表达，且其变化趋势与病变细胞凋亡和炎症反应及骨溶解病情密切相关；针对细胞内或细胞外GRP78/Bip的靶向治疗在骨溶解动物模型中存在差异，且其治疗效果与骨溶解病变程度明显相关。因此我们提出GRP78/Bip信号通路在病变细胞内和细胞外的作用机制假说，并用此假说合理解释GRP78/Bip信号通路在不同疾病中表现出不同作用，甚至在相同疾病中也表现出不同作用的原因。本项目根据该假说设计实验，从临床、动物模型和细胞学三个层次阐明GRP78/Bip信号通路在假体周围骨溶解中的作用机制，及靶向调节细胞内外GRP78/Bip对骨溶解病程进展的影响，并通过病变组织移植动物模型来验证其靶向治疗的有效性。

The GRP78/Bip is involved in most of the stress response, and has the characteristics of tissue specificity and developmental stages. The GRP78/Bip can migrate out of the endoplasmic reticulum (ER) into the nucleus (intracellular protein) and to the cell surface (extracellular protein).Thus BiP conforms to the definition of a true moonlighting protein with two quite distinct roles in vivo. There are some divergences of views on the research of GRP78/Bip, and the specific cell biological mechanism remains to be clarified. Our preliminary experimental results showed that the GRP78/Bip was consistently highly expressed inside and outside the cell at the same time, and its trend was closely related to apoptosis, inflammation and the progression of osteolysis. Therefore, we propose a hypothesis for the intracellular and extracellular mechanisms of GRP78/Bip signaling pathway, and it could be one reason that different diseases behave so differently in people, and why even diseases of the same type vary dramatically from person to person. According to the hypothesis, this project elucidates the mechanism of GRP78/Bip signaling pathway on particles-induced periprosthetic osteolysis mainly from three levels—molecular cell, animal model, and clinical observation, and elucidates the effects and therapeutic strategy of targeting intracellular and extracellular GRP78/Bip on the progression of osteolysis. In the absence of any model that might accurately predict the success, or failure, of a biological agent, a xenogeneic model with a severe combined immunodeficient mouse has been used to test the efficacy of the targeted therapy in order to provide a new idea for the prevention and treatment of periprosthetic osteolysis.