Hippo-YAP/TEAD信号通路在创伤性脑损伤中的作用与机制研究

Apoptosis plays an important role in secondary brain injury following traumatic brain injury. The Mst1(Hippo)-YAP pathway and the YAP/TEAD pathway are involved in the inflammatory response and apoptosis processes in many diseases. It is speculated that Mst1-YAP/TEAD signaling pathway may participate in the pathological process of secondary brain injury after TBI. Therefore, we hypothesize that after TBI, Mst1 activates YAP, blocking the binding of YAP to TEAD and activating the apoptotic signaling pathway, thereby aggravating brain injury. To verify this hypothesis，we used a rat TBI model to intervene the interaction of Mst1 and YAP using recombinant Mst1, siRNA interference and YAP overexpression to observe brain injury. In addition, western blot, immunofluorescence staining and ELISA were used to detect the expression and activation of key factors of signaling pathways, to analyze the possible molecular mechanism of Mst1-YAP/TEAD signaling pathway in regulating secondary brain injury following TBI, provide a new direction and theoretical basis for the prevention and treatment of secondary brain injury after TBI.

细胞凋亡在创伤性脑损伤（TBI）后继发性脑损伤中发挥重要作用。Mst1(Hippo)-YAP通路和YAP/TEAD通路参与许多疾病的炎症反应和细胞凋亡过程。推测Mst1-YAP/TEAD信号通路可能参与TBI后的继发性脑损伤的病理过程。因此，我们提出假说：TBI后，Mst1磷酸化YAP，阻碍YAP进入细胞核与TEAD结合，不能促进一些促存活因子和抑制一些凋亡因子的转录，凋亡信号通路激活，加重脑损伤。为了验证该推论：我们使用大鼠TBI模型，应用重组Mst1、siRNA干扰技术及YAP过表达等措施干预Mst1与YAP的相互作用，观察脑损伤情况。另外，利用western blot、免疫荧光染色、ELIISA等手段, 检测信号通路关键因子的表达和激活情况，分析探讨Mst1-YAP/TEAD信号通路调控TBI后继发性脑损伤可能的分子作用机制，为防治TBI提供新方向和理论依据。

创伤性脑损伤（TBI）是一种高发病率、致残率、致死率的神经外科急症，是目前国际上主要关注的公共卫生和社会经济问题之一。TBI 是一个复杂的病理生理过程，它涉及炎性反应、细胞凋亡、血脑屏障破坏、脑缺血和神经退行性疾病等众多机制。从病理生理学角度上，TBI 大致可分为两个阶段：原发性脑损伤和继发性脑损伤。原发性损伤源于环境中机械外力直接作用于颅骨和脑，瞬间造成脑部神经细胞死亡，属于不可逆的机械损伤。因此，深入认识 TBI 后继发性脑损伤的病理生理反应，针对其机制，寻找有效防治脑外伤的潜在靶点，是降低 TBI 致死、致残率的关键。本项目主要从炎症、凋亡和线粒体功能三个方面探讨了TBI后继发性脑损伤发生机制。TBI后，我们发现Sec22b通过上调自噬水平对细胞死亡发挥保护作用；线粒体膜外蛋白线粒体Rho-GTPase 1 (Miro1)通过促进线粒体转运途径对继发性脑损伤起神经保护作用；WNK3激酶通过抑制NKCC1的磷酸化来对抗继发性脑损伤的发生；另外，Bmal1 (brain and muscle Arnt-like protein-1)可降低TBI后的炎症和水肿。这些发现为TBI治疗提供了重要的参考依据。