MAM相关IP3R/GRP75/VDAC1通路介导慢性间歇低氧致内皮细胞损伤机制研究

阻塞性睡眠呼吸暂停综合征（OSAS）是心血管疾病的独立危险因素，其关键机制是慢性间歇低氧(CIH)所致血管内皮损伤。线粒体相关内质网膜(MAM)是线粒体及内质网功能偶联的结构基础，广泛参与钙信号调控，介导内质网-线粒体功能偶联。IP3R/GRP75/VDAC1复合体构成MAM中最为重要的钙转运通道，在多种疾病的发生发展中起重要作用。本课题组前期研究表明CIH诱导血管内皮细胞线粒体依赖性凋亡；同时发现CIH可诱导细胞发生内质网应激。然而内质网-线粒体功能偶联在CIH相关内皮细胞损伤中的作用尚未见报道。本课题拟从内质网-线粒体功能偶联的角度出发，利用体内/体外实验探索MAM参与CIH相关内皮细胞损伤机制，并探索CIH下IP3R/GRP75/VDAC1通路在内质网-线粒体功能偶联中的作用，为全面阐述OSAS心血管损伤机制并寻找相关治疗靶点奠定基础。

Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular diseases (CVD). That chronic intermittent hypoxia (CIH) induced vascular endothelial injuries is the key mechanism. The specific sites of physical association between the endoplasmic reticulum (ER) and mitochondria are known as mitochondria-associated endoplasmic reticulum membranes (MAM), which is crucial for efficient transmission of Ca2+ from the ER to mitochondria, thus controlling the function of ER and mitochondria, and determining cell fate. IP3R/GRP75/VDAC1 complex constitutes the most important Ca2+ transport channel in MAM. As we previously demonstrated endothelial cells mitochondrial apoptosis under CIH. We also found that CIH could lead to ER stress. Combined with literature, we presume that IP3R/GRP75/VDAC1 meadiates ER stress-MAM-mitochondrial dysfunction plays a critical factor in CIH-induced cell injury. Therefore, this research will lucubrate the underlying mechanism of IP3R/GRP75/VDAC1 in affecting mitochondrial functions and ER stress, thus regulating cell fate by using animal and cellular vascular endothelial injury models under CIH, and also explore changes in MAM constituents PACS-2, Mfn2, MCU, SERCA, Sig1R and so on, to establish a regulatory network of endothelial cell injury induced by CIH. It should be meaningful to clarify the specific mechanisms of OSAS related cardiovascular complications, and provide the basis for further studies and finding targeted drug.