低氧诱导因子1对上气道扩张肌低氧损伤的生物学机制研究

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a chronic disorder characterized by intermittent and recurrent upper airway (UA) obstruction during sleep, associated with hypoxia and hypercapnia which have deleterious consequences on physical health and quality of life. UA dilator muscles may be the key point in the study of pathogenesis and therapy of OSAHS. Long term hypoxia can cause damage to UA dilator muscles and trigger a vicious cycle. When muscle gets injury, myoblasts are activated and differentiate into myocytes in order to repair injured muscle. Hypoxia plays a major role in causing many abnormalities associated with OSAHS. HIF-1α (hypoxia-inducible factor 1α) has been identified as the master regulator for cellular adaptation to hypoxia. In preliminary study, we verified that HIF-1α up-regulation mediates the muscle fatigue in hypoxia condition and inhibits differentiation of myoblasts. In addition, hypoxia activates AMPK pathway which is involved in myogenic differentiation. In previous research, the regulatory relations between HIF-1α and AMPK pathway remain controversial, and few research have been made on skeletal muscle. This research is proposed to explore the aforementioned controversy on skeletal muscle by experiments in vitro and transgenic mice model. The mechanism and related signalling pathways of UA dilator muscle injury caused by hypoxia are to be revealed in mitochondrial biogenesis, energy metabolism, fiber type transition and autophagy. In addition, the protection and underlying biological mechanism of estrogen-like drugs will be investigated.

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）是睡眠中间歇性反复发生的上气道阻塞，伴有通气不足和呼吸暂停，引发慢性缺氧、低氧血症和睡眠结构紊乱。上气道扩张肌是研究OSAHS发病机制与治疗途径的关键，长期低氧能损伤上气道扩张肌，并引发恶性循环。肌损伤时，成肌细胞激活并分化融合成肌管以修复损伤。HIF-1α是细胞处于低氧环境的主要调节因子。课题组前期研究证实，HIF-1α上调介导了低氧条件下的肌疲劳，抑制成肌细胞分化；同时，低氧能激活AMPK通路，后者参与成肌细胞分化。目前，HIF-1α和AMPK通路究竟存在怎样的调控关系还存在争议，在骨骼肌领域少有研究。本课题拟在骨骼肌领域探索HIF-1α和AMPK通路的调控关系，通过体外实验和转基因动物模型体内验证，从线粒体发生、能量代谢、肌纤维转换和自噬等方面研究上气道扩张肌低氧损伤的机制及相关信号通路，并对药物保护上气道扩张肌功能的机制作深入探索。

阻塞性睡眠呼吸暂停低通气综合征(OSAHS)是睡眠中间歇性反复发生的上气道阻塞,伴有通气不足和呼吸暂停,引发慢性缺氧、低氧血症和睡眠结构紊乱。OSAHS的病因比较复杂，从发病机制分析主要包括上气道解剖结构狭窄和上气道扩张肌功能障碍。上气道扩张肌是研究OSAHS发病机制与治疗途径的关键,长期低氧能损伤上气道扩张肌,并引发恶性循环。肌损伤时, 成肌细胞激活并分化融合成肌管以修复损伤。HIF-1α是细胞处于低氧环境的主要调节因子。本课题证实了HIF-1α对OSAHS的调控作用,通过体外实验和转基因动物模型体内验证,从线粒体发生、能量代谢和自噬等方面研究了上气道扩张肌低氧损伤的机制及相关信号通路,并对药物保护上气道扩张肌功能的机制作了深入探索。体外研究发现,低氧环境下HIF-1α表达增多介导了成肌细胞分化抑制, MRFs表达降低，自噬水平下降，线粒体超微结构破坏，线粒体生物发生受到抑制，AMPK可能通过下调HIF-1α来增加PGC-1β的表达进而增加线粒体的生物发生。体内研究发现，慢性间歇性低氧（CIH）损伤了小鼠颏舌肌的超微结构，HIF-1α的骨骼肌条件性敲除减轻了小鼠颏舌肌超微结构的损伤，恢复了Egr-1、Smad3和Id3等蛋白的表达水平，保护了颏舌肌功能。研究还发现，白藜芦醇二聚体能部分恢复CIH导致的颏舌肌超微结构损伤，增加颏舌肌自噬水平，增加线粒体生物发生，降低凋亡水平，该保护作用可能与AMPK相关。目前临床上对于OSAHS的治疗主要针对解剖结构狭窄，对上气道扩张肌功能障碍缺乏有效的治疗方法。相信随着该项研究的深入，OSAHS的发病机制进一步得到阐明，白藜芦醇二聚体的研究也为将来药物治疗提供实验依据。