ER/Hippo信号传导通路crosstalk抑制创伤性脑损伤细胞凋亡的分子机制

Traumatic brain injury nowadays is a severe public health issue in China. Our previous published data shows that ER signaling pathway plays an anti-apoptotic role in pericontusional edema zone via its non-genomic and genomic effects. Further, our previous data indicated that YAP1 enhanced the apoptosis in pericontusional edema zone and the over-expression of YAP1 blocked the anti-apoptotic role in pericontusional edema zone. In addition, the pre-treatment of estrogen induced the phosphorylation of YAP1 at the early post-traumatic stage and decreased the expression of YAP1 mRNA slightly at the late stage. In contrast, the protein expression of YAP1 dramatically decreased at the late stage after the pre-treatment of estrogen. Therefore, according to the literature, we speculate that estrogen might enhance the degradation through the ubiquitination. Thus, we expect to testify that the existence of ER pathway and Hippo pathway crosstalk through the pre-treatment of estrogen, the interference of ER and YAP1 and so on in Sprague Dawley rats after the overiectomy. The supposed mechanism is that estrogen mediated YAP1 to play an anti-apoptotic role in the pericontusional edema zone via the phosphorylation of YAP1 at the early post-traumatic stage and via the down-regulation of YAP1 expression and the protein degradation of YAP1 by ubiquitination at the late stage. This project might underline the novel mechanism of traumatic brain injury regulated by YAP1, the downstream target and co-activator of Hippo pathway, and improve the development of new chemical targeting on YAP1.

创伤性脑损伤已成为中国严重的公共卫生问题。我们已发表实验结果表明雌激素受体（ER）信号传导通路可通过非基因组效应和基因组效应在脑挫裂伤外周水肿带起抗细胞凋亡作用。前期研究证实YAP1促进脑挫裂伤外周水肿带细胞凋亡；YAP1过表达可抑制雌激素的抗凋亡作用；雌激素预处理促进外伤早期YAP1磷酸化，部分降低后期YAP1 mRNA表达，而明显降低后期YAP1蛋白表达，因此结合文献推测雌激素可能促进后期YAP1泛素化降解。因此我们希望利用去势大鼠脑挫裂伤模型，通过雌激素预处理及人为干扰ER和YAP1等，证实ER信号通路和Hippo信号通路存在crosstalk，其具体机制可能为：外伤早期雌激素经非基因组效应磷酸化YAP1，后期则经下调YAP1表达和促进泛素化降解，起抗凋亡作用。该研究为以YAP1为主的Hippo通路在脑损伤调节机制的阐明提供全新思路，为开发以YAP1为新靶点的脑保护剂奠定理论基础。

创伤性脑损伤已成为严重的公共卫生问题，脑挫裂伤中心区及脑挫裂伤外周水肿带（pericontusional edama zone）可发生神经元和神经胶质细胞凋亡，深入开展有关脑损伤后细胞凋亡机制的研究，可为寻找针对细胞凋亡的靶向药物奠定理论基础，对脑保护药物的开发及降低创伤性脑损伤死亡率和病残率具有重要的临床和现实意义。本研究探讨了Hippo信号转导通路核心蛋白YAP1可能通过调节凋亡蛋白Bax促进周围水肿带细胞凋亡，同时ER信号传导通路与Hippo信号转导通路之间存在crosstalk，YAP1可能为核心，介导17β雌二醇在脑挫裂伤外周水肿带中的抗细胞凋亡作用。17β雌二醇对YAP1的调控作用包括非基因组效应（具有Hippo信号转导通路依赖性的YAP1磷酸化作用）和基因组效应（调控YAP1 转录表达）。本研究为以YAP1为主的Hippo通路和ER信号传导通路在脑损伤抗凋亡机制的阐明提供全新思路，为开发以YAP1为新靶点的脑保护剂奠定理论基础。