亲环蛋白D参与调节神经元线粒体分裂/融合的分子机制的研究

项目名称： 亲环蛋白D参与调节神经元线粒体分裂/融合的分子机制的研究

项目编号： No.31271145

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 杜蘅

作者单位： 山东大学

项目金额： 85万元

中文摘要： 线粒体分裂及融合在维持神经元功能中起到重要作用，但是调控线粒体分裂/融合的机制目前尚未阐明。亲环蛋白D(cypD)是一种线粒体蛋白，参与调节线粒体钙吸收能力和氧自由基产生。我们前期实验发现cypD缺失的海马神经元轴突线粒体长度分布出现异常，并且cypD敲除小鼠脑内线粒体融合蛋白表达量显著升高。因此我们推测cypD参与调控神经元分裂/融合。为明确cypD在神经元线粒体分裂/融合中的调控作用，我们采用cypD基因改造动物构建cypD敲除或cypD高表达模型。我们首先从体内及体外研究在神经元静息状态及激活状态下，cypD对神经元线粒体形态的影响，进一步观察线粒体形态改变与线粒体功能的关系，最终研究cypD参与调控神经元线粒体分裂/融合的分子机制。本研究将对阐明cypD在调控神经元线粒体分裂/融合中的生理作用以及线粒体通过调节其形态和功能以适应神经元功能活性状态的机制提供实验及理论基础。

中文关键词： 亲环蛋白D；线粒体膜通透性复合孔；线粒体动力学；神经元；树突棘发育

英文摘要： Mitochondrial fusion and fission play an important role in maintaining neuronal function. However, the detailed mechanisms controlling mitochondrial fusion and fission are still largely unknown. Cyclophilin D (cypD) is a mitochondrial protein and involves in regulating mitochondrial calcium buffering capacity and reactive oxygen species production. Our priliminary data showed significant changes in the distribution of axonal mitochondrial length in cypD deficient hippocampal neurons. Furthermore, we found that cypD deficient mice demonstrated increased expression levels of mitochondrial fusion proteins. We thusly formed a hypothesis that cypD involves in neuronal mitochondrial fusion and fission regulation. To address the concept, we will employ cypD knockout, cypD overexpressing and non-transgenic mice. We will collect data from neuron at resting state or at stimulated state. Firstly, we will study the impact of cypD on axonal mitochondrial morphology; next we will study the relationship of mitochondrial morphology and function; finally we will determine the detailed mechanisms underlying the effect of cypD on mitochondrial fusion and fission. The findings of this study will have positive impacts on elucidating the physiological function of cypD in controlling mitochondrial fusion and fission; besides, the resu

英文关键词： cyclophilin D；mitochondrial permeability transition pore；miochondrial dynamics；neuron；dendritic spine morphogenesis