SIRT1-SOD2对创伤性脑损伤（TBI）后神经元线粒体损伤的调节机制

Neuronal mitochondrial damage caused by traumatic brain injury (TBI) plays an important role in secondary brain injury. Previous studies have confirmed that SIRT1 can reduce the mitochondrial damage caused by TBI via inhibiting the activation of p38 signal pathway, but the mechanism of SIRT1 regulating mitochondrial damage has not been fully elucidated. Reactive oxygen species (ROS) not only participates in TBI secondary injury, but also is the effective signal molecules to activate p38. SIRT1 is able to change the activity of the enzyme by regulating the expression and acetylation of superoxide dismutase 2 (SOD2), so as to control the ROS level. Our recent preliminary experiments showed that the decrease of SOD2 expression in TBI was accompanied by significant oxidative stress response, and the SOD simulation could reduce the mitochondrial damage. These suggest that SOD2 may participate in the regulation of SIRT1 on mitochondrial damage after TBI. So through specific chemical drugs, adenovirus vector, knockout mice and other means, this project is to explore whether SIRT1 achieve the regulation of neuronal mitochondrial injury after TBI by influencing the expression and acetylation of SOD2. This study will help us to reveal the regulating mechanisms of neuronal mitochondrial damage after TBI and provide a new theoretical basis for the treatment of TBI.

TBI导致的神经元线粒体损伤在继发性脑损伤中发挥了重要作用，课题组前期研究已经证实SIRT1可以通过抑制p38活化减轻TBI所致的线粒体损伤，但SIRT1调控线粒体损伤的具体机制还未完全阐明。ROS不仅参与TBI继发性损伤，也是活化p38的有效信号分子，SIRT1则能够通过调节SOD2的表达及乙酰化水平影响其酶学活性，实现对ROS水平的调控。课题组近期预实验显示，TBI后脑组织SOD2表达量下降伴随着明显氧化应激反应，SOD的模拟物则可改善线粒体损伤。这些提示我们SOD2可能介导了SIRT1对TBI后线粒体损伤的调节。为此，项目拟在细胞及动物模型上通过特异性化学药物、腺病毒载体以及基因敲除小鼠等手段探讨SIRT1是否通过影响SOD2表达和乙酰化水平，进而实现其对TBI后神经元线粒体损伤的调节。本研究将有助于揭示TBI后神经元线粒体损伤调节机制，为TBI的治疗提新的理论基础。

创伤性脑损伤（TBI）具有较高的致死率和致残率，目前仍然缺乏有效治疗手段，严重威胁人类健康。课题组前期发现，SIRT1介导的线粒体损伤调控可影响TBI的发生，但SIRT1在TBI发展中的具体机制还未完全阐明。. 课题组在本项目资助下，深入探讨了SIRT1在TBI中对神经元的保护机制。首先，项目利用非靶向代谢组学技术从代谢角度解析了SIRT1对TBI脑损伤早期神经组织代谢特征的调控效应，并进一步利用生物信息学分析了SIRT1的传统激动剂对TBI后脑组织代谢调控的潜在的分子机制。其次，课题组探讨了TBI后肠-脑轴相互作用的机制。初步探讨了SIRT1-SOD2在TBI继发性肠损伤中的保护效应。利用微生物组学和代谢组学明确了TBI后肠道菌群及肠道代谢物的变化特征。发现了肠道微生物代谢产物8-姜辣素（8G）在TBI脑损伤调控中的重要作用，证实了肠道菌群代谢物8G通过活化Parkin介导的线粒体自噬对TBI脑组织发挥反向保护性调节效应。在此基础上，项目还证实了TREM-1和NLRP3介导的细胞焦亡及炎症反应在TBI后脑损伤及继发性肺损伤中的共同作用机制。最后，项目扩展性探讨了SIRT1介导的神经元线粒体功能调节在脓毒症脑损伤中的效应。发现SIRT1可通过抑制p38 MAPK减轻脓毒症脑损伤中的神经元线粒体损伤、神经系统炎症反应和氧化应激。. 项目不仅进一步揭示了SIRT1在TBI器官损伤中的调节作用和机制，也发现了肠道代谢物8-姜辣素、TREM-1对TBI的新作用和分子机制。这为治疗TBI提供了新的靶点和理论依据。