间歇低氧所致海马神经细胞损伤中自噬的作用及其机制研究

Obstructive sleep apnea hypopnea syndrome (OSAHS) which is characterized by intermittent hypoxia can cause systemic injury. Although the injury to the nervous system has been confirmed by number of clinical and experimental studies, its causal mechanisms have not been clarified entirely. Autophagy as an important physiological mechanism to maintain cell homeostasis is also involved in neuronal injury. Early studies of Our team found that amounts of autophagosomes were peoduced in rat hippocampal neurons with intermittent hypoxia. We speculate that autophagy may be an importent mechanism of neuronal injury induced by intermittent hypoxia. However, studies on intermittent hypoxia and neuronal autophagy have not been retrieved. Therefore, on the basis of preliminary work, we further explore the relationship between intermittent hypoxia and neuronal autophagy by replicate cell and animal moders, attempt to determine the mechanism of autophagy activation, which involves conjunction between oxidative stress/hypoxia-inducible factor-1α (HIF-1α) stress related pathway and neronal autophagy, and then investigate the effects of antioxidant and drugs which can intervene the autophagy related pathway on neurons. The purpose of this study is to further elucidate the mechanism of intermittent hypoxia-mediated neuronal injury, which will lay a theoretical foundation for the prevention and treatment of OASHS.

以间歇低氧为特征的阻塞性睡眠呼吸暂停低通气综合征（OSAHS）可导致全身多系统的损害，其神经系统的损害已被大量临床和实验研究证实，但损害的具体机制尚未完全清楚。自噬（Autophagy）作为维持细胞稳定的重要生理机制，在神经细胞损伤中起重要作用。我们前期研究发现：间歇低氧处理的大鼠海马神经细胞内有大量自噬体产生，推断间歇低氧对自噬的影响可能是神经细胞损伤的重要机制。目前尚未检索到间歇低氧与神经细胞自噬的研究文章。本研究拟在已有工作基础上，通过间歇性低氧暴露大鼠和海马神经细胞，进一步探讨间歇低氧与神经细胞自噬的关系，研究间歇低氧影响神经细胞自噬的具体机制，包括氧化应激、低氧诱导因子-1α（HIF-1α）相关通道与神经细胞自噬的关联，观察抗氧化和药物干预神经细胞自噬相关通道对神经细胞的影响。本研究旨在进一步阐明间歇低氧所致神经细胞损伤的机制，为防治OSAHS所致神经细胞损伤奠定理论基础。

以间歇低氧为特征的阻塞性睡眠呼吸暂停（OSA）可导致全身多系统的损害，其神经系统的损害已被大量临床和实验研究证实，但损害的具体机制尚未完全清楚。自噬（Autophagy）作为维持细胞稳定的重要生理机制，在神经细胞损伤中起重要作用。本研究通过间歇性低氧暴露大鼠和体外培养的海马神经细胞，探讨了间歇低氧与神经细胞自噬的关系，分析了间歇低氧影响神经细胞自噬的具体机制，包括氧化应激、低氧诱导因子-1α（HIF-1α）相关通道与神经细胞自噬的关联，观察了药物干预神经细胞自噬相关通道对神经细胞的影响。结果发现：1.间歇低氧暴露可以诱导海马神经细胞自噬增多，且与间歇低氧程度呈正相关；2.间歇低氧诱导的海马神经细胞自噬增多是因为间歇低氧诱导了自噬激活；3.活性氧（ROS）和HIF-1α介导了间歇低氧诱导的海马神经细胞自噬激活；4.自噬诱导剂雷帕霉素诱导的自噬加重了间歇低氧所致海马神经细胞凋亡，自噬抑制剂氯喹和自噬相关蛋白的siRNA抑制自噬减轻了间歇低氧所致海马神经细胞凋亡。以上结果提示，自噬参与了间歇低氧诱导的海马神经细胞凋亡，间歇低氧诱导的海马神经细胞自噬激活是由ROS和HIF-1α所介导，自噬激活在间歇低氧致海马神经细胞凋亡中起损伤作用。这些研究表明抑制自噬可能是临床上防治OSA致认知障碍的重要策略之一。项目资助发表SCI收录论文10篇，中华系列期刊收录论文3篇，会议论文14篇。培养研究生5名。项目经费预算70万元，实际支出427798元，剩余272202元，结余经费计划用于本项目研究后续支出。