缺氧导致肺血管平滑肌线粒体稳态失衡是肺循环系统疾病发生、发展的关键环节，机制未明。我们的结果揭示：缺氧通过线粒体ROS 调控线粒体融合蛋白Mfn1/2影响线粒体的融合分裂动态平衡，导致线粒体形态、结构和功能异常。拟通过下述研究证明该假设：1缺氧诱导ROS的来源和种类，ROS在肺动脉平滑肌线粒体稳态失衡中的作用；2 ROS对Mfn1/2的调控,Mfn1/2在mROS 所致的线粒体稳态失衡中的作用；3 mROS 调控Mfn1/2的信号转导系统及蛋白质相互作用网络，明确ROS调控线粒体的分子机制和关键节点蛋白。研究结果将阐明缺氧对ROS的诱导作用及ROS对肺动脉平滑肌细胞Mfn1/2的影响；提出缺氧通过ROS调控线粒体Mfn1/2引起肺血管平滑肌线粒体稳态失衡的新机制。

Imbalance of mitochondrial homeostasis of pulmonary smooth muscle cells (PASMCs) induced by hapoxia is a key scientific problem of the pulmonary circulation diseases. Our results indicated that the hapoxia-indecued the imbalance of mitochondrial homeostasis is thourou ROS by regulating the expression of mitofusin-1/2, which causes functional and morphylogical abnormity of PASMCs mitichondria. We propose 3 specific aims to test the hypothesis: (1) to examine the sources and species of hypoxia-induced ROS; and the role of ROS in the imbalance of PASMC mitochondrial homeostasis under hypoxic condition, (2) to demonstrate the influence of hypoxia on the expression of mitofusin-1/2, and the role of mitofusin-1/2 in PASMC mitochondrial homeostasis induced by ROS, and (3) to identify signal transduction pathways, protien-protien interaction network involved in the regulation of in mitofusin-1/2 induced by mitochondrial ROS, and the underlying molecular key protiens and molcule mechanisms of the imbalance ofmitichondrial homeostasis induced by ROS. This project will significantly increase our understanding of the role of hypoxia on ROS production and function in PASMCs mitochondria, indentifying the molcule mechanisms of ROS regulating mitofusin-1/2, and is likely to shed insight into a novel mechanisms of hypoxia induced imbalance of mitochondrial homeostasis via ROS regulated mitofusin-1/2.