线粒体蛋白Sirt5对蛛网膜下腔出血后早期脑损伤的保护作用及机制研究

早期脑损伤（Early brain injury,EBI）是蛛网膜下腔出血（Subarachnoid Hemorrhage,SAH）后预后不佳的主要原因，而保护线粒体是减轻EBI的有效策略。Sirt5是线粒体内NAD+依赖的琥珀酰基转移酶，与代谢及氧化还原过程密切相关。我们预实验发现小鼠SAH后大量线粒体蛋白去琥珀酰化修饰，且与氧化磷酸化过程密切相关，生物信息学分析提示此现象可能受Sirt5调控；激活Sirt5 能促进蛋白去琥珀酰化并改善神经功能评分。我们推测Sirt5可能通过去琥珀酰化修饰激活代谢关键酶，改善线粒体功能，促进EBI恢复。本项目使用SAH动物和离体实验结合基因遗传学和药理学干预手段，探索Sirt5对能量代谢和氧化应激水平的影响，揭示Sirt5在EBI中的保护作用和机理，并以Sirt5为靶点寻找相关治疗药物。该项目将为SAH治疗以及开发新神经保护剂提供新靶标。

Early brain injury (EBI) is the main target for neuroprotection and protection of mitochondria is an effective strategy to alleviate EBI. Sirt5 is a NAD+-dependent succinyltransferase located in mitochondria, which plays an important role in mitochondrial metabolism and redox process. Here we have found that hundreds of proteins are desuccinylated after SAH in mice and these proteins are mainly located in mitochondria and are related to oxidative phosphorylation. Bioinformatics analysis suggests that Sirt5 may regulate this process. Further experiments show that the protein expression of Sirt5 increases after SAH; Sirt5 activator Resveratrol affects protein desuccinylation, and improves brain edema and neurological function scores after SAH. We hypothesize that Sirt5 may activate key metabolic enzymes through desuccinylation modification, improve mitochondrial function, and ameliorate EBI. In the present study, we will explore the effects of Sirt5 on brain energy metabolism and oxidative stress, investigate the signaling pathways, and prove the protection of Sirt5 in EBI. The project will provide new solution for the treatment of SAH patients and novel targets for the development of new neuroprotective agents.