线粒体心磷脂在颅脑外伤中的作用与机制研究

Traumatic brain injury (TBI) is the leading cause of death in children and young adults, and remains an incurable disease. TBI leads to both direct mechanical damage and functional disturbance in mitochondria, which are key mechanisms contributing to neuronal death after TBI. Therefore, prevention of mitochondrial damage and/or removal of dysfunctional mitochondria (mitophagy) are promising therapeutic strategies. In this current study, we will apply both in vitro and in vivo TBI modes to evaluate the role of cardiolipin of both mitophagy (mitochondrial autophagy) and apoptosis pathway after TBI. At the same time, we will try to develop imaging mass spectrometry of oxidative lipidomics and define spatial distribution of oxidizable and non-oxidizable phospholipids and postsynthetic oxidative modification of anionic phospholipids - CL and PS - in vulnerable brain regions after TBI. The primary purpose of this research proposal is to identify the detailed role of cardiolipin after TBI, which may serve as the foundation for clinical trials designed to improve outcome in TBI patients.

颅脑外伤严重危害患者的健康，目前尚无有效的治疗方法。我们根据前期工作基础提出：颅脑外伤后神经细胞线粒体心磷脂膜外翻诱发线粒体自噬现象，残留的受损的线粒体内心磷脂氧化产物的形成促使了细胞死亡的发生。我们认为及时清除已经发生功能障碍的线粒体并且保护完整的线粒体功能是重要的保护神经功能的手段。本项目拟通过体外细胞和在体动物模型，综合研究颅脑外伤后神经元细胞线粒体自噬和细胞凋亡与心磷脂的关系，同时，结合前期工作基础，我们拟通过质谱学和脂质学绘制颅脑外伤后脂质质谱脑功能全图，为全面认知颅脑外伤后的发病机理，开发基于线粒体心磷脂的靶向治疗颅脑外伤的药物提供理论依据。

颅脑外伤严重危害患者的健康，目前尚无有效的治疗方法。我们根据前期工作基础提出：颅脑外伤后神经细胞线粒体心磷脂膜外翻诱发线粒体自噬现象，残留的受损的线粒体内心磷脂氧化产物的形成促使了细胞死亡的发生。我们认为及时清除已经发生功能障碍的线粒体并且保护完整的线粒体功能是重要的保护神经功能的手段。本项目通过体外细胞和在体动物模型，综合研究颅脑外伤后神经元细胞线粒体自噬和细胞凋亡与心磷脂的关系，证明颅脑外伤后的氧化应激反应，炎症反应，凋亡过程线都与粒体自噬密切相关。并且，这一过程同样也受到心磷脂的调控。因此，后续的研究可以通过研究靶向心磷脂的药物或小分子抑制剂来检测其在颅脑外伤后神经元的修复作用。相关结果已经发表在Journal of Pineal Research，Journal of Neurotrauma，Experimental Neurology，Biochimica et Biophysica Acta-Molecular Basis of Disease等国外期刊。