脂联素调控内质网应激对间歇低氧诱导的颏舌肌能量代谢、细胞凋亡及肌纤维功能改变的影响及机理研究

Genioglossal dysfunction is a key pathogenesis of obstructive sleep apnea syndrome (OSAS). Our previous studies demonstrated that a)chronic intermittent hypoxia (CIH) could lead to hypoadiponectinemia, cellular mitochondrial dysfunction and apoptosis in genioglossus; b) supplement of adiponectin could improve the pathological damages mentioned above. However, the concrete mechanisms have not be completely elucidated. Some study revealed that ischemia/reperfusion, a pathological condition like CIH, could cause lasting excessive endoplasmic reticulum stress (ERS), which could futher result in mitochondrial dysfunction and cellular apoptosis. Our prelimilary study has implicated that it is highly possible that ERS existed in genioglussal cells under CIH. We therefore speculate that the genioglussal cellular mitochondrial dysfunction and apoptosis under CIH are very possibly associated with CIH induced ERS. Through investigating the associated machanisms from ERS to mitochondrial dysfunction and to cellular apoptosis, as well as the intervention role of adiponectin, this study will be of great help in further elucidating the patogenesis of OSAS and in providing theoretic basis for innovation of novel drugs for OSAS.

颏舌肌功能异常是阻塞性睡眠呼吸暂停综合征(OSAS)的重要发病机制，我们前期研究表明，慢性间歇性低氧(CIH)会诱导颏舌肌细胞的线粒体功能障碍及凋亡，而补充外源性脂联素（Ad）可缓解该病理损伤，近期又发现CIH可引起颏舌肌纤维收缩功能降低。由于Ad具有抑制ERS的功效，ERS又是细胞凋亡和能量代谢障碍的重要前奏。近年研究显示类似CIH的缺血/再灌注会诱导心肌细胞发生持续过度的内质网应激（ERS），从而导致线粒体机能障碍和心肌细胞凋亡和收缩障碍。我们的初步研究提示CIH环境下颏舌肌的线粒体功能障碍和细胞凋亡及肌纤维收缩功能低下极可能与CIH诱导的ERS相关。而Ad的保护机制也极可能与调控了CIH引发的ERS有关。本课题通过探讨CIH环境下Ad调控ERS对大鼠颏舌肌线粒体功能障碍、细胞凋亡和肌纤维收缩功能改变的干预效应和机理，不仅有助于进一步阐明OSAS的发病机制，也为设计新药提供理论依据。

颏舌肌作为上气道最主要的扩张肌，其功能异常是导致阻塞性睡眠呼吸暂停低通气综合征(OSAHS)的重要发病机制。由于慢性间歇性低氧（CIH）是OSAHS重要病理特征，本课题选择CIH大鼠模型的颏舌肌为研究对象，探讨CIH对颏舌肌的影响及其损伤机制，尤其是CIH对颏舌肌细胞内质网应激（ERS）及通路、细胞凋亡及其功能的影响以及补充外源性脂联素的干预作用和机理。研究显示，CIH可引起颏舌肌细胞线粒体损伤、ERS及细胞凋亡增强和收缩及抗疲劳功能减退，而补充外源性脂联素可通过调节AMPK通路缓解CIH诱导的ERS而改善颏舌肌病理及功能改变。该发现对于进一步阐明OSAHS的发病机制和临床上使用脂联素治疗OSAHS引起颏舌肌损伤提供了理论依据。