睡眠碎片化抑制GPX4诱导铁死亡导致术后谵妄的机制研究

Postoperative delirium (POD) is a major neurological complication in the perioperative period of elderly patients. While sleep fragmentation (SF) is a widespread phenomenon in the elderly patients, but the correlation between them is still unclear. Our previous studies have found that chronic sleep deprivation can lead to cognitive decline at 6h, 9h after surgery in elderly mice, decreased GPX4 in the hippocampus, impaired mitochondrial respiratory chain function, and increased ferroptosis. Given the importance of GPX4 pathway in regulating mitochondrial function and ferroptosis, we put forward the following hypothesis: SF inhibits GPX4, which leads to enhanced mitochondrial stress reaction, and enhanced ferroptosis linked to the positive feedback, which can lead to POD. The study intends to identify the correlation between acute or chronic SF and POD from animal level and clinical level. The intact mitochondria were extracted from the tissue, and the oxygen consumption rate will be tested by new technology XF24. The purpose is to reveal the effects of mitochondrial respiratory chain after the inhibition of GPX4 in elderly mice. In addition, with tool medicine of targeted GPX4 and the conditional hippocampus, forehead and cerebellar regions of GPX4 BIKO knockouted mice, It is clarified systemly that ferroptosis mediated by GPX4 is the main regulation mechanism of SF leading to POD, and it provides new ideas for POD prevention and treatment.

术后谵妄（POD）是老年患者围术期主要神经系统并发症，而老年患者围术期普遍存在睡眠碎片化（SF）现象，但两者相关性仍不清楚。我们前期研究发现：慢性睡眠剥夺可导致老年小鼠术后6h,9h认知下降。进一步预实验发现：SF可至海马区GPX4降低，线粒体呼吸链功能受损，铁死亡增加。鉴于GPX4通路在调节线粒体功能和铁死亡中的重要作用。提出以下假说：SF通过抑制GPX4通路，导致线粒体内ROS增加和应激反应增强，后者进一步抑制GPX4，形成正反馈触发铁死亡，从而导致POD发生。本研究拟从动物、临床等多层次明确急、慢性SF与POD的相关性；采用新技术测组织完整线粒体的氧消耗率，揭示抑制GPX4对线粒体呼吸能力和应激的影响；应用GPX4的工具药和条件性海马、前额、小脑等脑区GPX4 BIKO基因敲除小鼠，系统阐明GPX4介导的铁死亡是SF导致POD的主要调控机制，为POD的防治提供新思路。

术后谵妄（POD）是老年患者围术期主要神经系统并发症，老年患者围术期普遍存在睡眠碎片化（SF）现象，我们的研究发现：慢性睡眠剥夺可导致老年小鼠术后认知下降。进一步实验发现：SF可致海马区GPX4降低，线粒体呼吸链功能受损，铁死亡增加。SF通过抑制GPX4通路，导致线粒体内ROS增加和应激反应增强，后者进一步抑制GPX4，形成正反馈触发铁死亡，从而导致POD发生。本研究从动物、细胞、分子等多层次明确急、慢性SF与POD的相关性；采用新技术测组织完整线粒体的氧消耗率，揭示抑制GPX4对线粒体呼吸能力和应激的影响。系统阐明GPX4介导的铁死亡是SF导致POD的主要调控机制，为POD的防治提供新思路。