SENP1抑制间歇低氧引起的小胶质细胞炎症及其神经元保护作用

Obstructive sleep apnea syndrome (OSAS) can cause neurorecogtive dysfunction associated with intermittent hypoxia (IH). However, the concrete pathogenesis has not been elucidated. Recent studies have shown that IH could result in inflammation and impairment of microglia, which can further lead to neurorecogtive dysfunction. Our recent studies indicated that IH could induce activation of microglia and upregulation of cytokines via NF-кB/p38MAPK pathway, accompanied with reduced expression of Sentrin/SUMO-specific protease 1 (SENP1). With excessive expression of SENP1 in vitro from microglia, the inflammatory level decreased and neuronal apoptosis improved. The studies are still lacked about the mechanisms through which SENP1 regulate microglia inflammation and neuronal impairment. We speculate that it is highly possible that SENP1 takes part in IN-induced microglia inflammation and neuronal impairment through the pathways of HIF-1α as well as ROS, iNOS and other cytokines. Through the SENP1+/- mice model and excessice expression of SENP1 in microglia, we plan to investigate the molecular mechanisms about how SENP1 are involed in IH induced microglia inflammation, impairment and neurocogntive dysfunction. Therefore, this study is available to further understand the pathogenesis of neurocogtive dysfunction in OSAS patient and to provide theoretic basis and potential target for corresponding prevention and treatment.

阻塞性睡眠呼吸暂停综合征（OSAS）可致神经认知功能障碍，这与间歇低氧（IH）有关，具体机制尚未阐明。近年研究发现IH造成小胶质细胞炎症损伤神经元构成了认知功能障碍的基础。我们前期研究显示IH通过NF-кB/p38MAPK途径激活小胶质细胞释放炎性因子，并伴有SUMO特异性蛋白酶1（SENP1）表达下降；而小胶质细胞过表达SENP1后，炎症反应受抑制，与小胶质细胞共培养的神经元凋亡得以改善。但SENP1是通过何种机制调节小胶质细胞炎症反应及神经元损伤尚缺乏相应研究。我们推测SENP1可能影响iNOS、HIF-1α的SUMO化修饰调控其信号通路进而影响IH条件下小胶质细胞炎症及神经元损伤。本研究拟在小胶质细胞中过表达SENP1并利用SENP1基因敲除小鼠，探讨SENP1在IH诱导小胶质细胞炎症、损伤及认知功能障碍中的分子机制，为进一步认识OSAS认知功能障碍发生机制和防治提供理论基础和靶点。

阻塞性睡眠呼吸暂停综合征(OSAS)患者常并发神经认知功能障碍，这与间歇低氧（IH）有关，具体机制尚未阐明。本研究证实 IH可促进小胶质细胞SUMO特异性蛋白酶1（SENP1）表达下降，导致NF-B/p38MAPK信号通路和调控小胶质细胞迁移、吞噬的关键蛋白发生SUMO化，释放炎性因子诱导小胶质细胞迁移、吞噬、凋亡，神经元凋亡，引起神经认知功能障碍。NF-κB必须调节蛋白（NF-κB-essential modulator，NEMO）和TOM1 (target of Myb1) 蛋白的SUMO化在其中起着重要作用。本研究目的已达到，结果对于阐明SENP1在IH诱导小胶质细胞炎症、迁移、吞噬、凋亡和神经元A沉积、凋亡及OSAS患者认知功能障碍中的作用有重要指导价值。围绕本课题，已发表SCI论著4篇（其中2篇第一标注），中文核心期刊综述1篇，全国性会议交流综述1篇，全国性会议交流获奖论文1篇。另有2篇SCI论著已完成在投稿中（均第一标注）。