lncRNA XIST/miR-494/mTOR信号通路对脊髓损伤的调控及机制研究

Spinal cord injury (SCI) is a type of trauma with poor prognosis and high morbidity. It course severe disease burden, and reduce the patient's life quality. Spinal cord injury in local tissues after apoptosis, autophagy aggravate is an important pathological link causing neuronal damage, inhibition of apoptosis and autophagy has become an important target to promote neural function recovery after spinal cord injury. With the development of high-throughput sequencing and expression chip technologies, non-coding RNAs have been found to be involved in the development and progression of various diseases. Early construction of this project through the construction of SCI rat model and found that PI3K/Akt/mTOR in spinal cord injury tissue was abnormally expressed, induced neuronal apoptosis and autophagy. Combined with the results of RNA expression chip and differential-expressed gene expression analysis, it has been suggested the interaction between long-chain non-coding RNAlncRNA-XIST and microRNA miR-494 may mediate the regulation ofPI3K/Akt/mTOR expression. This project aims to further reveal the molecular mechanism of lncRNA-XIST / miR-494-mediated PI3K/Akt/mTOR signaling pathway in spinal cord injury through bioinformatics analysis, behavioral observation and cell function determination. The research may provide a theoretical basis and reference for the prevention and treatment of spinal cord injury

脊髓损伤临床预后较差、致残率高，造成严重的疾病负担，严重影响患者生活质量。脊髓损伤后局部组织中细胞凋亡、自噬加剧是造成神经元损伤的重要病理环节。随着高通量测序和表达芯片技术的发展，发现非编码RNA参与细胞凋亡和自噬、是脊髓损伤的新靶点，但其调控机制有待研究。本项目前期通过构建脊髓损伤大鼠模型，发现PI3K/Akt/mTOR在脊髓损伤组织中异常表达，诱导神经元发生细胞凋亡和自噬，结合RNA表达芯片和基因表达差异分析，提示lncRNA-XIST可能通过miR-494介导PI3K/Akt/mTOR的表达调控。本项目拟通过生物信息学分析、行为学观察和细胞凋亡/自噬功能鉴定，进一步揭示脊髓损伤中lncRNA-XIST/miR-494介导凋亡和自噬相关的PI3K/Akt/mTOR信号通路的分子调控机制，为设计新的脊髓损伤防治药物提供一定的理论基础和参考依据。

脊髓损伤后大量神经细胞缺失而新生神经元不能有效补充，损伤部位的炎症反应长期持续存在，致使其功能难以恢复。本项目突破既往研究方法，另辟蹊径，以临床神经外科脊髓髓内占位患者为研究对象，利用新型微量定量质谱方法对手术所致脊髓损伤病患的术前及术中脑脊液蛋白进行检测，来源于数量非常有限的临床脑脊液样本的组学数据及多模临床数据无法通过简单的数据分析获得有效可靠的信息，通过整合脊髓手术全病程临床表现，影像学等信息，进行高维建模回归分析，获得可以提示脊髓损伤病理进程及再生修复的生物分子标记物组及相关评估模型。进而利用人源神经干细胞及其衍生功能细胞系统解析脑脊液中调控脊髓修复的关键因子及其相关细胞分子机制。项目将通过这两方面的工作建立脊髓损伤风险评估预警系统，并探索促进脊髓修复再生的新机制，及脊髓损伤后再生修复的新策略与新方案。