酮体β-羟丁酸调控Redox稳态及线粒体反向电子传递减轻心肺复苏脑损伤的机制研究

心肺复苏（CPR）后缺氧缺血性脑损伤（HIBI）是心脏骤停（CA）患者死亡和长期神经功能丧失的主要原因。近期研究提示酮体具有神经保护作用。课题组预实验也发现，生酮饮食喂养小鼠CA/CPR后神经功能显著改善，但机制不明。本课题拟通过动物及细胞模型，整合13C-NMR同位素分析、代谢组学、代谢流、蛋白翻译后修饰等多种研究层面及技术，探讨酮体β-羟丁酸（β-OHB）对CA/CPR后HIBI的保护作用，层层揭示酮体β-OHB增强磷酸戊糖途径（PPP），并通过组蛋白酮体Kbhb修饰正向调控谷氨酸半胱氨酸连接酶（GCL）转录，协同促进还原型谷胱甘肽（GSH）生物合成，调控氧化还原（Redox）稳态；同时酮体β-OHB抑制线粒体呼吸链反向电子传递（RET），直接减少线粒体活性氧（ROS）生成，共同作用减轻CA/CPR后HIBI。本项目的成功实施将为CA/CPR后HIBI的防治措施提供新的思路和理论基础。

Hypoxic ischemic brain injury (HIBI) after cardiopulmonary resuscitation (CPR) is a leading cause of mortality and long-term neurological disability in cardiac arrest (CA) patients. Recently, it is suggested that ketone body may provide neurological protection. Meanwhile, we previously found that the neurological function after CA/CPR in mice fed with ketogenic diet was significantly improved. However, the mechanism of this metabolic change and its pathophysiological role in CA/CPR are still unclear. In this study, we intend to build the animal and cell models and integrate 13C-NMR isotope analysis, metabolomics, 13C-flux, post-translational modification of protein to explore the protective effect of ketone body. We will reveal that ketone body exerts the protection against HIBI after CA/CPR by enhancing the antioxidant mechanism, which is the result of promoting the glutathione (GSH) biosynthesis through upregulating the transcription of acid cysteine ligase (GCL) by histone Lysine β-hydroxybutyrylation (Kbhb) and through the enhancement of pentose phosphate pathway (PPP), and by the inhibition of the reverse electron transport (RET) of mitochondrial respiratory chain, which can reduce the production of ROS. This research will provide novel view and theoretical foundation of an attractive therapeutic target for HIBI after CA/CPR.