阻塞性睡眠呼吸暂停患者对低氧环境适应的表观遗传学机制研究

We recently found that some highlanders, particularly Tibetans, who suffer from obstructive sleep apnea (OSA), could have extremely long duration of OSA events (the longest one even reached at 6.3 min-long). This reflects that the patients with OSA live in different environment may have different characteristics in OSA events among different races and individuals. This finding provides a unique clue for the research in epigenetic mechanism for patients with OSA in adaptation to hypoxic environment. Hypoxia inducible factor-1α(HIF-1α) and its downstream signal pathway of HIF-1α-VEGF/EPO regulated by genes and proteins are the key pathways to regulate amount of red blood cells via affecting the levels of vascular endothelial growth factor and erythropoietin, in responses to hypoxia. In the current proposal, we plan to use the research tools of epigenetic, molecular biology, disease attributes and mathematical model, focusing on the roles of HIF-1α-VEGF/EPO signal pathway in epigenetic mechanism to reverse the OSA symptoms, to explore positively rapid responses of molecular gene regulatory network in responses to environmental challenges. The outcomes of research would be valuable in further understanding the pathological mechanisms of OSA, the evaluation of its clinical significance, searching target organism for effective treatment and providing data in new research direction.

我们近期发现，部分高原居民，尤其是藏族的阻塞性睡眠呼吸暂停（Obstructive Sleep Apnea，OSA）患者有异常增高的血红蛋白和异常延长的OSA事件（最长达6.3分钟）。表明，随OSA患者生存环境不同，OSA事件的特征有显著种族和个体差异。这一发现对探讨OSA病人对低氧环境适应的表观遗传学研究提供了独特线索。缺氧诱导因子1α（HIF-1α）及其下游的基因与蛋白所形成的HIF-1α-VEGF/EPO 信号通路是调控细胞低氧应答，影响血管内皮生长因子和促红细胞生成素，以调节红细胞生成的关键通路。本研究将通过表观遗传学、分子生物学、疾病特征及数学模型等四个方面的研究，阐明调控HIF-1α-VEGF/EPO信号通路逆转OSA缺氧症状的表观遗传学机制，探索有助于快速应对环境改变的分子基因调控网络，为深入了解OSA的病理机制及临床评估和寻找有效治疗的生物靶标奠定理论基础及提供指导方向。

阻塞性睡眠呼吸暂停（Obstructive sleep apnea, OSA）是最常见的睡眠呼吸障碍，患者生存海拔环境不同，OSA事件的特征可能存在显著种族和个体差异。本项目紧密围绕这一关键问题，充分利用我国高海拔资源优势，应用具有国际前沿水平的研究技术，采用多模态的研究策略，从疾病特征、神经功能、分子生物学及基因遗传等方面对不同海拔地区健康受试、OSA患者及模型小鼠进行独立及比较分析。建立了高海拔及低海拔地区OSA综合数据库；阐明了不同海拔地区OSA患者的临床及功能特征、种族差异和遗传基础；明确了夜间氧疗等特殊治疗对高海拔OSA患者的有效性；在患者与模型动物之间建立起一种能够从神经功能和疾病特征机制深入研究OSA靶器官损害的转化研究模式，旨在探寻靶器官损害的有效防治方案。为深入了解海拔变化对OSA的病理机制及临床评估和寻找有效治疗的生物靶标奠定理论基础及提供指导方向。