PI3K-Akt-mTOR信号通路介导的自噬对脊髓损伤后神经元细胞凋亡的影响及其机制的研究

Apoptosis is a important feature of secondary spinal cord injury. Except for neuronal apoptosis, autophagy also has been documented to participate in the pathological process following secondary damage. Previous researches have showed the fundamental effects of autophagy on secondary spinal cord injury by surpressing the neuronal apoptosis. However, the mechanisms remain controversial. PI3K-Akt-mTOR signaling pathway is one of important intracellular signaling pathways, which has important biological effects on the process of apoptosis and autophagy. Several studies have showed both autophagy and apoptosis could be dominated by PI3K-Akt-mTOR signaling pathway. And autophagy can regulate neuronal apoptosis through PI3K-Akt-mTOR signaling pathway. In this study, inhibitators of mTOR, PI3K and Akt, will be performed in rat model of spinal cord injury to intervene the PI3K-Akt-mTOR signaling pathway. We plan to answer the following questions: whether upregulation of autophagy can play important role in expression of neuroal apoptosis following acute spinal cord injury; whether the effects of activated autophagy through PI3K-Akt-mTOR signaling pathway on apoptosis is dependent on mitoautophagy, which inhibits the mitochondrional pathway of apoptosis, or activated Akt, or synergistic effects of both mechanisms. The purpose of this work is to highlight the effects of induction of autophagy folliowing spinal cord injury.

凋亡是脊髓继发性损伤的重要组成部分。除凋亡以外，自噬也已被证实参与脊髓继发性损伤的病理生理过程。研究证实自噬对急性脊髓损伤后神经细胞凋亡的有重要作用，但自噬对神经细胞凋亡的作用机制目前仍不明确。PI3K-Akt-mTOR信号通路是细胞内非常重要的信号转导途径，在细胞凋亡和自噬等过程中发挥着极其重要的生物学作用。自噬与凋亡可共同受制于PI3K-Akt-mTOR信号通路调控，PI3K-Akt-mTOR通路可能参与自噬对脊髓损伤后神经元细胞凋亡的调控。本项目拟在大鼠脊髓损伤模型上，采用mTOR抑制剂雷帕霉素，PI3K抑制剂3-MA，Akt抑制剂IV干预PI3K-Akt-mTOR信号通路，阐明自噬对急性脊髓损伤后神经细胞凋亡的影响；并阐明PI3K-Akt-mTOR信号通路介导的自噬对神经细胞凋亡效应，是否通过受损线粒体自噬或活化Akt，或者是二者的协同效应引起。

凋亡是脊髓继发性损伤的重要组成部分。除凋亡以外，自噬也已被证实参与脊髓继发性损伤的病理生理过程。先前的研究证实自噬对急性脊髓损伤后神经细胞凋亡的有重要作用，但自噬对神经细胞凋亡的作用机制目前仍不明确。PI3K-Akt-mTOR信号通路是细胞内常重要的信号转导途径，在细胞凋亡和自噬等过程中发挥着极其重要的生物学作用，自噬与凋亡可共同受制于PI3K-Akt-mTOR信号通路调控。本次课题研究证实PI3K-Akt-mTOR通路参与自噬对脊髓损伤后神经元细胞凋亡的调控。PI3K-Akt-mTOR 信号通路介导的自噬可通过清除受损线粒体抑制脊髓损伤后神经元细胞凋亡的线粒体途径，并且PI3K-Akt-mTOR信号通路在脊髓损伤中的作用机制，不仅依赖于自噬的表达，也有活化Akt的参与。