THE PARKINSONIAN 6 HYDROXYDOPAMINE MODEL

描述（申请人摘要）：帕金森病是最常见的 老年人群的衰弱性运动障碍。的神经元 帕金森氏病的退化受到增加的氧化应激 因为在多巴胺释放的过程中， 新陈代谢. 6-羟基多巴胺（6-OHDA）是氧化还原循环多巴胺类似物， 其可以被靶向选择性地破坏黑质纹状体系统， 帕金森氏症的退化。磷酸酪氨酸信号通路 由神经保护因子如脑源性神经营养因子激活 和胶质细胞源性神经营养因子，是重要的多巴胺能 神经元功能和存活。本提案旨在调查 氧化剂介导的磷酸酪氨酸信号转导改变假说 导致帕金森病中多巴胺能神经元的变性。 硝基酪氨酸，涉及过氧亚硝酸盐形成的氧化应激的标志物， 在6-OHDA啮齿动物模型和人帕金森病脑中均增加 组织中过氧亚硝酸盐是由超氧化物与硝酸反应形成的 氧化物，暗示这些自由基在帕金森氏症的发病机制 疾病在这一建议中，6-OHDA，超氧化物和硝酸盐 氧化物影响磷酸酪氨酸信号级联将研究使用 永生多巴胺能神经元系和具有遗传改变水平的小鼠 细胞外超氧化物歧化酶这套全面的研究将 对氧化应激的机制产生重要的见解， 影响多巴胺能神经元的神经营养信号， 促进抗氧化剂-神经营养因子联合的发展 帕金森病的治疗方法

DESCRIPTION (applicant's abstract): Parkinson's disease is the most common debilitating movement disorder of the aging human population. The neurons that degenerate in Parkinson's disease are subject to increased oxidative stress because superoxide and other reactive species are generated during dopamine metabolism. 6-hydroxydopamine (6-OHDA) is a redox cycling dopamine analog, which can be targeted to selectively damage the nigrostriatal system that degenerates in Parkinson's disease. Phosphotyrosine signaling pathways activated by neuroprotective factors, such as brain derived neurotrophic factor and glial cell line-derived neurotrophic factor, are important for dopaminergic neuron function and survival. This proposal is designed to investigate the hypothesis that oxidant-mediated alterations in phosphotyrosine signaling contribute to degeneration of dopaminergic neurons in Parkinson's disease. Nitrotyrosine, a marker of oxidative stress involving peroxynitrite formation, is increased in both the 6-OHDA rodent model and in human Parkinsonian brain tissues. Peroxynitrite is formed from the reaction of superoxide with nitric oxide, implicating these free radicals in the pathogenesis of Parkinson's disease. In this proposal, mechanisms by which 6-OHDA, superoxide, and nitric oxide affect phosphotyrosine signaling cascades will be investigated using immortalized dopaminergic neuron lines and mice with genetically altered levels of extracellular superoxide dismutase. This comprehensive set of studies will yield important insights concerning mechanisms by which oxidative stress affects neurotrophic signaling in dopaminergic neurons, potentially contributing to development of combined antioxidant-neurotrophic factor therapies for Parkinson's disease.