Snapin介导神经元晚期内体轴突转运调控线粒体自噬在脑外伤后神经保护作用的机制研究

脑外伤（TBI）具有高发病率、高死亡率和高致残率的突出特点，但目前尚缺乏安全有效的治疗措施。线粒体自噬作为线粒体质量控制的关键细胞途径在脑外伤后神经元重建稳态中发挥了重要作用。但脑外伤后线粒体自噬功能障碍的分子机制尚不清楚。基于申请人前期工作基础，推测TBI后线粒体自噬功能障碍可能是由突触小体相关蛋白（Snapin）介导晚期内体轴突转运障碍导致溶酶体功能缺陷引起的。本项目拟利用小鼠TBI模型和神经元牵拉损伤模型，采用time-lapse活细胞成像及膜分离技术等开展：①建立线粒体自噬失调与线粒体轴突运输受损在TBI后神经元损伤的机制联系；②阐明Snapin介导晚期内体运输对自噬溶酶体功能的直接影响是TBI后神经元线粒体稳态维持的关键环节；③提出逆转TBI后神经元线粒体病理和神经元死亡的可操控机制。通过上述研究，为揭示TBI后脑保护作用机制提供理论依据，有望为TBI治疗与预后判断提供新的思路。

Traumatic brain injury (TBI) is a leading cause of mortality, morbidity, and disability in the world. To date, there is no effective treatment to promote functional recovery for TBI. Mitophagy, as a key cellular pathway for mitochondrial quality control, plays an important role in the restoration of neuronal homeostasis after TBI. However, the molecular mechanism of mitophagy dysfunction after TBI is unknown. Based on the applicant's previous work, it is speculated that mitophagy dysfunction after TBI may be caused by lysosomal function defects which is regulated by synaptosome-associated protein (Snapin)-mediated axonal transport of late endosomal. This project is designed to carry out in vivo and in vitro using time-lapse live cell imaging and membrane separation technology as follows: ① To establish a mechanistic link between mitophagy deregulation and impaired axonal transport of mitochondria in a mouse model of TBI; ②To test the hypothesis that impaired transport of snapin-mediated late endosomes is associated with disrupted loading of lysosomes with critical proteases as an underlying core aspect in the maintenance of neuronal mitochondrial homeostasis after TBI; ③ To elucidate an operative mechanism reversing neuronal mitochondrial pathology and neuronal death after TBI. Based on the above studies, this proposal is expected to provide a new theoretical basis for the protective mechanism after TBI, and to provide new strategies and ideas for the treatment and prognosis of TBI patients.