从线粒体动力学角度研究氢气治疗重度脓毒症的具体机制

项目名称： 从线粒体动力学角度研究氢气治疗重度脓毒症的具体机制

项目编号： No.81471842

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 谢克亮

作者单位： 天津医科大学

项目金额： 72万元

中文摘要： 重度脓毒症是危重病患者的主要死因，尚无有效治疗方法。申请人已发表的结果证实2%氢气有效改善重度脓毒症小鼠的存活率和器官功能，与激活Nrf2/HO-1通路密切相关，但具体机制仍不清。线粒体动力学（融合/分裂）平衡是维持线粒体形态和功能的关键因素，其平衡紊乱是脓毒症发病机制的重要环节，与Nrf2/HO-1有关。因此，本课题假设：氢气通过激活Nrf2/HO-1通路调控线粒体动力学平衡发挥对重度脓毒症的保护作用。本项目拟利用野生型和Nrf2基因敲除型小鼠，采用血管内皮细胞模型和重度脓毒症动物模型，通过检测线粒体融合/分裂、自噬和生物合成的相关分子表达，线粒体形态和功能，从线粒体动力学角度阐明氢气治疗脓毒症的具体机制，进一步探讨Nrf2/HO-1在此过程中的作用，明确氢气通过激活Nrf2/HO-1通路调控线粒体动力学平衡发挥对重度脓毒症的保护作用，为氢气治疗脓毒症提供理论依据，为其临床应用奠定基础。

中文关键词： 重度脓毒症；氢气；线粒体动力学；Nrf2/HO-1通路；线粒体生物合成

英文摘要： Severe sepsis is the leading cause of death in critically ill patients with no effective therapeutic method available. My published results prove that 2% hydrogen gas can effectively improve the survival and organ function in mice with severe sepsis, which is closely correlated with activation of Nrf2/HO-1 pathway. However, the detailed mechanisms are still unclear. The balance of mitochondrial dynamics (fusion/fission) is critical to the morphology and function of mitochondria, and its impaired balance plays an important role in development of sepsis, which is also correlated with Nrf2/HO-1 pathway. Therefore, we hypothesized that hydrogen gas can protect against severe sepsis through Nrf2/HO-1 pathway activation-induced balance of mitochondrial dynamics. In this study, using wild-type and Nrf2 knockout mice, we will firstly investigate that hydrogen gas can regulate mitochondrial dynamics balance in the treatment of severe sepsis through measurement of the mitochondrial fusion/fission, mitophagy and biogenesis, as well as mitochondrial morphology and function in mice (severe sepsis) and in vascular endothelial cells (a cell culture model of sepsis). Furthermore, we will investigate the roles of Nrf2/HO-1 pathway in this process. In conclusion, we will prove that hydrogen gas can protect against severe sepsis through Nrf2/HO-1 pathway activation-induced balance of mitochondrial dynamics, which provides a theoretical basis for hydrogen treatment in sepsis and lays a foundation for its clinical application.

英文关键词： Severe sepsis;Hydrogen gas;Mitochondrial dynamics;Nrf2/HO-1 pathway;Mitochondrial biogenesis