Beclin-1通过线粒体自噬及ECD结构域调节脊髓损伤过程中细胞焦亡的机制研究

脊髓损伤往往继发于脊柱骨折，是一种发病率高、致残致死率高的脊柱外科疾病，病理机制复杂、临床治疗困难。申请人前期已阐明多种细胞死亡形式在脊髓损伤病理过程中的作用机制（Fan J et al: J Neurotrauma 2018, Aging 2019, J Neuroinflammation 2020, FASEB J 2020），并推测：Beclin-1蛋白通过影响NLRP3炎性小体活性调控细胞焦亡。本研究拟运用免疫共沉淀和酵母双杂实验等方法，利用已构建的多种条件性基因敲除小鼠和临床标本，从细胞、动物及临床循序渐进地证实：Beclin-1蛋白不仅可通过ECD结构域芳香族指状结构与NLRP3炎性小体NACHT结构域直接结合，亦可通过线粒体自噬间接影响NLRP3炎性小体活性。本研究是脊髓损伤理论体系的重要补充，有助于更系统、更全面地阐明脊髓损伤的病理机制，并为临床治疗提供新方法、新思路。

Spinal cord injury is often caused by spine fracure,is a clinical disease with a high morbidity, disability, and mortality. Clinical treatment is very difficult due to its complicated pathological mechanism. The mechanism of various cell death forms in the pathological process of spinal cord injury has been elucidated in the previous studies（Fan J et al: J Neurotrauma 2018, Aging 2019,J Neuroinflammation 2020,FASEB J 2020）in conjunction with striking up speculation that Beclin-1 protein regulates pyroptosis by affecting the activity of NLRP3 inflammasome. Attempting to employ the methods of immunoprecipitation and yeast two-hybrid experiment as well as the existing multiple conditional gene knockout mice and clinical specimens, the study sets out to prove it from cells, animals and clinical treatment progressively: Apart from directly binding to NLRP3 inflammasome NACHT domain through ECD domain aromatic fingerlike structure, Beclin-1 still vicariously affects NLRP3 inflammasome activity through mitochondrial autophagy. Redounding to set forth the pathological mechanism of spinal cord injury more systematically and comprehensively, the study offers supplement for improving the theoretical system of spinal cord injury with providing new methods and ideas for the clinical treatment of spinal cord injury.