THE PARKINSONIAN 6 HYDROXYDOPAMINE MODEL

描述(申请人摘要)：帕金森氏症是最常见的 使人衰弱的老年人口运动障碍。这些神经元 帕金森氏症退行性疾病易受氧化应激增加的影响 因为在多巴胺的作用下会产生超氧化物和其他活性物质 新陈代谢。6-羟基多巴胺(6-OHDA)是一种氧化还原循环多巴胺类似物， 其靶点可以选择性地损害黑质纹状体系统 在帕金森氏症中退化。磷酸酪氨酸信号通路 被脑源性神经营养因子等神经保护因子激活 和胶质细胞源性神经营养因子，对多巴胺能有重要作用 神经元功能和存活率。这项提案旨在调查 氧化剂介导的磷酸化酪氨酸信号改变假说 导致帕金森氏病的多巴胺能神经元退化。 硝基酪氨酸是氧化应激的标志，与过氧亚硝酸盐的形成有关。 在6-羟基多巴胺啮齿动物模型和帕金森病患者脑中均增加 纸巾。过氧亚硝酸盐是由超氧化物和一氧化氮反应生成的。 氧化物，表明这些自由基参与了帕金森病的发病机制 疾病。在本提案中，6-OHDA、超氧化物和一氧化氮的作用机制 氧化物影响磷酸酪氨酸信号级联的研究将使用 永生化的多巴胺能神经元系和基因水平改变的小鼠 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了重要的见解 潜在地影响多巴胺能神经元的神经营养信号 促进复合抗氧化剂-神经营养因子的发展 帕金森氏症的治疗方法。

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.