氧化应激介导经颅高压电烧伤PTSD的发病机制

hysiological and molecular mechanisms underlying behavioral and cognitive symptoms of post-traumatic stress disorder (PTSD) caused by Transcranial high-voltage electrical burn (THVEB) are not well understood and there is no definitive treatment and no cure for PTSD in clinic. We have identified that oxidative stress could induce imbalanced exoression of multiple miRNAs using chip technology, and some of them could potentially regulate the expression of retinoic acid related orphan receptor α (RORα), of which functional changes are closely related to the onset of PTSD. In this proposal, the oxidative stress biomarkers will be detected in patients with THVEB related PTSD (THVEB-PTSD)and animal models of THVEB-PTSD firstly to assess the correlation between PTSD and oxidative stress levels. Then the molecular mechanisms of oxidative stress-induced brain injury in pathogenesis of THVEB-PTSD will be investigated through p53-induced apoptosis pathway and post-transcriptional regulation of RORα expression by miRNAs pathway at the molecular, cellular, and the whole body level. Finally, the amelioration of PTSD-like symptoms by intervention of antioxidants, p53 specific inhibitor and RORα agonist were observed in an animal model of THVEB-PTSD. The goal of this proposal is to clarify the molecular mechanisms of oxidative stress-induced brain injury in pathogenesis of THVEB-PTSD and provide new targets for the prevention and treatment, as well as the biomarkers for early diagnosis of THVEB-PTSD.

经颅高压电烧伤致创伤后应激障碍（PTSD）的发病机制至今未明，临床上缺乏有效治疗措施。我们采用芯片技术发现氧化应激可诱导多个miRNAs表达失衡，部分miRNAs可潜在调控维甲酸相关孤儿受体α（RORα）表达，而RORα功能改变与PTSD发病密切相关。本课题首先在经颅高压电烧伤PTSD患者和动物模型体内检测氧化应激标志物，确定氧化应激与经颅高压电烧伤PTSD发病的相关性；然后在分子、细胞和整体水平分别从p53诱导细胞凋亡和miRNA在转录后调控RORα表达两个途径探讨氧化应激诱导脑损伤引起PTSD发病分子机制；最后在经颅高压电烧伤PTSD动物模型上分别采用抗氧化剂、p53特异性抑制剂和RORα激动剂针对性干预，观察模型鼠PTSD样症状改善情况。从氧化应激损伤角度阐明经颅高压电烧伤PTSD发病分子机制，为经颅高压电烧伤所致PTSD的临床防治提供早期诊断生物标志物和治疗靶点。

高压电烧伤是具有长期身体和心理影响的灾难性事件，电伤愈合后往往遗留机体功能障碍及心理异常，创伤后应激障碍（Post traumatic stress disorder, PTSD）则是电烧伤后并发的心理异常之一，已受到外科学界的关注。PTSD是烧伤病人心理研究领域里重要课题之一，而高压电烧伤所致 PTSD的研究则处于起步阶段，其确切分子机制尚不清楚。本课题首先制作经颅高压电烧伤致PTSD大鼠模型，为后续的机制研究奠定模型基础。然后在经颅高压电烧伤PTSD患者和动物模型体内检测氧化应激标志物，发现在高压电烧伤致PTSD患者和动物模型体内存在ROS、MDA、CAT等氧化应激生物标志物的高表达。此外通过在PTSD模型鼠海马中检测ROS含量，JNK、p53等相关凋亡蛋白的表达，明确高压电烧伤可通过ROS-JNK-p53通路诱导海马神经元凋亡参与氧化应激损伤致高压电烧伤PTSD发生发展的病理过程。最后通过外源性给与抗氧化剂NAC和p53抑制剂PFT-α，能够抑制海马神经元细胞凋亡，改善高压电烧伤动物模型的PTSD症状，为经颅高压电烧伤所致PTSD的临床防治提供早期诊断生物标志物和治疗靶点。