通过Tafazzin调控线粒体脂质氧化应激修复在颅脑创伤中的机制研究

Tens of millions of people are influenced by traumatic brain injury per year globally, and there is still no effective therapy by now. In previous studies, it is found that craniocerebral trauma will result in cardiolipin injury and remodeling, including oxidation, hydrolysis, acyl transfer and other processes, oxidative metabolism of lipid and lipid repair will influence the long-term neural function recovery prognosis. We think that complete description of changes to oxidative metabolism of cardiolipin after trauma, the process of intervention in lipid oxidation and remodeling, up-regulation of Tafazzin (Taz) during remodeling and reduction of degradation in mitochondria are helpful for the repair of neurocyte mitochondrial membrane phospholipid, and finally helpful for brain function recovery. This project, through cell and animal craniocerebral trauma models, aims to utilize related mass spectrum technologies to analyze and draw lipid mass spectrum brain function total graphs at different time points and in different parts and to detect the expression levels of proteins related with lipid oxidation and remodeling at the same time, and attempts to intervene mitochondrial protease’s reduction of Taz degradation and prove the role of Taz for brain trauma prognosis and recovery in the gene regulation animal experiment. The research results of this project will be helpful for complete understanding of the pathophysiological process of lipid and oxydrolysis remodeling metabolites after craniocerebral trauma, be helpful for development of targeted drugs for cardiolipin repair, and provide theoretical guidance for brain trauma drug therapy schemes.

全球每年有数千万人受到颅脑创伤的影响，至今仍缺乏有效的治疗方法。先前的研究发现颅脑创伤会导致线粒体心磷脂损伤重塑，其中包含氧化、水解、酰基转移等过程，脂质氧化代谢和脂质修复将影响到远期神经功能恢复预后。我们认为完整的描绘出线粒体脂质氧化代谢（尤其是心磷脂）在外伤后的变化，干预脂质氧化重塑过程，上调重塑过程中的Tafazzin（Taz）、减少其在线粒体中降解有助于神经细胞线粒体膜磷脂修复，最终有助于脑功能恢复。本项目拟通过细胞与动物颅脑创伤模型，利用相关质谱技术分析绘制外伤后不同时间点及部位的脂质质谱脑功能全图，同时检测脂质氧化重塑相关蛋白表达水平，并尝试干预线粒体蛋白酶减少Taz降解，在基因调控动物实验中验证Taz对脑外伤预后恢复的作用。本项目研究成果将有助于全面认知颅脑外伤后脂质及其氧化水解重塑代谢物的病理生理过程，有助于线粒体磷脂修复的靶向药物开发，并为脑外伤药物治疗方案提供理论。

全球每年有数千万人受到颅脑创伤的影响，至今仍缺乏有效的治疗方法。先前的研究发现颅脑创伤会导致线粒体心磷脂等脂质损伤重塑，其中包含氧化、水解、酰基转移等过程，脂质氧化代谢和脂质修复将影响到远期神经功能恢复预后。我们认为完整的描绘出脂质氧化代谢（尤其是心磷脂）在外伤后的变化，干预脂质氧化重塑过程，减少其在线粒体中降解有助于神经细胞膜磷脂修复，最终有助于脑功能恢复。本研究中我们通过细胞与动物颅脑创伤模型，利用相关质谱技术分析绘制外伤后不同时间点及部位的脂质图谱，对心磷脂等脑特异性脂代谢进行性了深入分析，我们同时检测脂质氧化重塑相关基因检测，并干预心磷脂重塑通路，在基因调控动物实验中验证了干预心磷脂代谢通路对脑外伤预后恢复的作用。在本课题中我们提供了线粒体心磷脂过氧化反应和水解反应的证据，这两个过程是脑外伤线粒体损伤致病机制的重要组成部分。这表明，从心磷脂氧化调节到水解调节的时间—剂量疗法可能对脑外伤的预后情况得到改善。同时在我们研究过程中也发现许多超预期结果，在外伤后脂质氧化代谢上，肝脏、血液系统或许也起到较为重要作用。