帕金森氏病是一种常见的神经退行性疾病。其典型的病理特征是中脑黑质的多巴胺神经元细胞的退行变性。线粒体功能障碍和氧化损伤在诱导多巴胺神经元细胞的死亡中起着极为关键的作用。保持线粒体DNA的稳定和基因的表达调控对维持线粒体和细胞的的正常功能十分关键。我们最近的研究发现，神经毒素鱼藤酮和重金属锰抑制线粒体DNA的复制和转录。本项目拟采用鱼藤酮制备的帕金森病大鼠模型以及体外细胞培养对线粒体DNA的复制转录以及线粒体DNA氧化损伤的调节机制进行进一步研究。通过纯化线粒体，研究不同底物激活下线粒体通透性转换孔的功能以及线粒体DNA氧化损伤，并研究这些改变的持续和可逆性以及淫羊藿苷对线粒体功能和氧化损伤的保护作用。通过体外细胞培养，采用药理和遗传学手段操控PGC-1α的表达研究PGC-1α调控线粒体基因的表达和线粒体DNA氧化损伤的分子机制，寻找信号通路中的关键调控因子，为研究和开发民族药提供新思路。

Parkinson's disease is a common neurodegenerative disease. The typical pathological features are substantia nigra dopamine neuron degeneration. Mitochondrial dysfunction and oxidative damage play a critical role in dopamine neuronal cell death. Stable expression and regulation of mitochondrial DNA genes are very important for maintaining the normal function of mitochondria and cells. Our recent study demonstrated that neurotoxins rotenone and manganese inhibit mitochondrial DNA replication and transcription. This project intends to adopt a rat model of rotenone-induced Parkinson's disease and utilize in vitro cell culture to further study the mitochondrial DNA replication and gene expression as well as the mechanism of oxidative mitochondrial DNA damage. Through purified mitochondria we will study mitochondrial permeability transition pore and mitochondrial DNA oxidative damage, and explore the reversibility of these changes. Moreover, we will investigate the protective effects of national medicine Icariin on mitochondrial function and oxidative DNA damage. By in vitro cell culture, we will genetically and pharmacologically manipulate expression of PGC-1α to further study the regulation mechanism of mitochondrial gene expression and oxidative damage, thus understand the role of PGC-1α signaling in neurotoxin rotenone-induced dopamine neuronal cell death.