内质网应激激活PERK/Nrf2信号通路负性调节氧化应激在关节纤维化中的作用机制研究

Joint contracture is a severe complication of post-trauma and external fixation. The pathogenesis of joint contracture is still obscure. Our preliminary experimental results demonstrated that endoplasmic reticulum stress (ERS) and oxidative stress would be involved in the pathogenesis of joint contracture. Furthermore, we figured out that ERS-related PERK/Nrf2 signaling pathway was activated by phosphorylation in joint contracture. Since phosphorylated Nrf2 is the inhibitor of oxidative stress, we infer that ERS-activated PERK/Nrf2 signaling pathway negatively regulates joint contracture by surpressing oxidative stress. Based on our previous study, we will systematically employ the technics including immunoprecipitation and protein array, to analyze the mechanisms of ERS, oxidative stress and PERK/Nrf2 signaling pathway in joint contracture, and to figure out the negative effect of Nrf2 by surpressing oxidative stress. New data from these experiments, not only help to elucidate the mechanisms of joint contracture, but also shed new light on the biological treatment for joint contracture.

关节纤维化是关节创伤及外固定后常见的严重并发症，目前发病机制未明确。我们的前期研究发现，内质网应激和氧化应激均参与了关节纤维化的发病过程，但两者具体的调控机制仍未清楚。我们进一步的研究表明，关节纤维化过程中内质网应激关键通路PERK/Nrf2信号通路被磷酸化激活，而磷酸化的Nrf2可抑制氧化应激反应。因此，我们提出内质网应激激活PERK/Nrf2信号通路负性调节氧化应激，从而抑制关节纤维化的假说。本研究拟采用免疫共沉淀、蛋白芯片等检测方法，旨在探索在关节纤维化发病过程内质网应激和氧化应激的相互作用机制及PERK/Nrf2信号通路的调控机制，明确Nrf2通过负性调控氧化应激抑制关节纤维化的作用，为确立关节纤维化新治疗靶点带来新的突破。

按照项目研究计划，课题组围绕关节纤维化的发病机制及相关蛋白开展研究，基本完成了预期的研究内容及研究目标，取得了阶段性的进展。课题组以大鼠关节纤维化动物模型为研究基础，研究发现氧化应激激活Nrf2高表达可通过抑制成纤维细胞铁死亡缓解关节纤维化，同时进一步发现内质网应激相关蛋白PTEN可通过PI3K/Akt/mTOR信号通路抑制关节纤维化；在关节纤维化的治疗方面，课题组研究发现透明质酸-姜黄素可通过增强PTGER2表达缓解关节纤维化的进程。课题组在项目执行期间取得了以下成果：本项目实际共发表SCI论文6篇，培养研究生共4名，已按计划完成项目。