Sirt4调节MnSOD去乳酸酰化在颅脑创伤中的作用及机制研究

颅脑损伤（TBI）后脑血流灌注异常诱发的乳酸堆积是继发脑损伤的重要原因，且血、脑乳酸水平与TBI患者的预后密切相关，但其机制尚不明确。我们近期研究发现TBI后脑组织中一种由糖酵解介导的蛋白酰化反应—乳酸酰化修饰显著增高；通过乳酸酰化质谱分析，发现线粒体上的超氧化物歧化酶MnSOD在TBI后出现明显的乳酸酰化修饰；进一步筛选发现线粒体去乙酰化酶Sirt4可能参与线粒体蛋白的去乳酸酰化调节。据此我们提出假说，TBI后大量堆积的乳酸导致线粒体蛋白MnSOD乳酸酰化修饰，降低了其抗ROS的活性，导致线粒体氧化应激损伤，诱发神经元死亡。本课题拟综合应用蛋白修饰组学、蛋白酶生物学、分子生物学等研究手段，阐明TBI后Sirt4调控MnSOD去乳酸酰化参与TBI继发脑损伤的作用及机制，为TBI的转化治疗提供新思路。

The accumulation of lactate induced by abnormal cerebral blood perfusion after head injury (TBI) is an important cause of secondary brain injury, and blood and brain lactate levels are closely related to the prognosis of TBI patients, but the mechanism is not clear. Our recent study found that glycolysis mediated protein lactylation modified and significantly increased in brain tissue after TBI. Through lactylation mass spectrometry analysis, we found that the superoxide dismutase MnSOD on the mitochondria could be obvious lactylation modified after TBI. Further screening found that the mitochondrial deacetylase Sirt4 may be involved in the regulation of mitochondrial protein delactylation. Based on this, we hypothesize that the large amount of lactate accumulated after TBI causes the lactylation of the mitochondrial protein MnSOD, which reduces its anti-ROS activity, leads to mitochondrial oxidative stress damage and induces neuronal death. This project intends to comprehensively apply protein modification omics, protease biology, molecular biology and other research methods to clarify the role and mechanism of Sirt4 regulating MnSOD delactylation after TBI to participate in the secondary brain injury of TBI and provide new ideas for the conversion therapy of TBI.