Sox9-Hif1α在上气道扩张肌低氧耐受中的作用机制研究

Obstructive sleep apnea hypopnea syndrome (OSAHS) is characterized by repeated obstruction of the upper airway during sleep and is an independent risk factor for stroke, heart disease and cancer. The largest muscle to maintain upper airway dilation is genioglossus, known as the "upper airway safety muscle". OSAHS patients suffer from chronic intermittent hypoxia due to upper airway obstruction. The genioglossus is not tolerant of hypoxia, which leads to aggravation of airway obstruction caused by falling tongue. Our group’s previous studies have confirmed that mice genioglossus is sensitive to oxygen, but the mechanism of genioglossus hypoxic injury and hypoxic tolerance is not very clear. In this study, we compared naked mole rat, which is high hypoxia-tolerant animal, with mouse and found that the hypoxia inducible factors HIF1α and SOX9, the main regulators of maintaining oxygen homeostasis, were highly expressed. HIF1α and SOX9 may have synergistic effects on enhancing hypoxia tolerance of genioglossus. Under the chronic intermittent hypoxia, in vivo and in vitro experiments were conducted to study the interaction of SOX9-HIF1α in regulating hypoxic injury of genioglossus by using naked mole rats, mice and genioglossus-derived stem cell lines. Our group will screen and confirm the key molecule of Sox9-Hif1α regulating hypoxic tolerance, the molecular mechanism of naked mole rat resisting OSAHS injury. At the same time we will study and try to reduce hypoxic injury of genioglossus. This project will provide some theoretical basis for the mechanism of genioglossus hypoxic injury and the therapeutic study of upper airway obstruction in OSAHS.

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）以睡眠时上气道反复阻塞为特征，是中风、心脏病和癌症的独立危险因素。维持上气道扩张的最大肌肉是颏舌肌，称“上气道安全肌”。OSAHS患者因上气道阻塞处于慢性间歇性低氧，颏舌肌不耐低氧，损伤后导致舌体下坠气道阻塞加重。课题组前期研究证实小鼠颏舌肌对氧敏感，但颏舌肌低氧损伤和耐受机制并不十分清楚。本课题组利用超耐低氧动物裸鼹鼠对比小鼠，发现维持氧稳态的主调器低氧诱导因子HIF1α和SOX9高表达，且二者可能在增强颏舌肌低氧耐受中有协同性。拟模拟慢性间歇性低氧，通过体内体外实验，利用裸鼹鼠、小鼠及颏舌肌肌源性干细胞系，研究SOX9-HIF1α在调控颏舌肌低氧损伤中的互作关系，筛选确认Sox9-Hif1α调控低氧耐受的关键分子，阐明裸鼹鼠颏舌肌抵抗OSAHS损伤的分子机制，为降低低氧损伤的机制研究和减缓OSAHS患者上气道阻塞的治疗研究提供理论依据。

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）以睡眠时上气道反复阻塞为特征，是中风、心脏病和癌症的独立危险因素。维持上气道扩张颏舌肌，称“上气道安全肌”。OSAHS患者因上气道阻塞处于慢性间歇性低氧，颏舌肌不耐低氧，损伤后导致舌体下坠气道阻塞加重。课题组前期研究证实小鼠颏舌肌对氧敏感，但颏舌肌低氧损伤和耐受机制并不十分清楚。本项目已利用超耐低氧动物裸鼹鼠对比小鼠，发现维持氧稳态的主调器低氧诱导因子HIF1α和SOX9高表达，HIF1α信号通路可能在增强颏舌肌低氧耐受中有协同性。本项目已按计划模拟OSAHS式的慢性间歇性低氧，通过体内体外实验，利用小鼠及颏舌肌肌源性干细胞系，研究了HIF1α在调控颏舌肌低氧损伤中的互作关系，并已完成如下研究内容：A.上气道扩张肌在低氧下的损伤；B.不同年龄阶段上气道扩张肌的损伤和耐受特征；C.肌源性干细胞衰老状态；D. Noggin因子如何影响上气道扩张肌；E. 具多种分化潜力的牙髓干细胞（DPSCs）；F. Noggin联合牙髓干细胞促进上气道扩张肌肌源性干细胞的成肌分化机制；G. 不同氧气浓度处理的条件下，敲除低氧诱导因子HIF1a对成肌细胞内线粒体等细胞器的超微结构影响和作用；H. HIF-1a在细胞凋亡过程中负调控AMPK促进成肌细胞分化并保护线粒体的完整性，提示 HIF-1a在低氧耐受中的功能。为降低颏舌肌低氧损伤的机制研究和减缓 OSAHS 患者上气道阻塞的治疗研究提供了理论依据和研究基础。