THE PARKINSONIAN 6 HYDROXYDOPAMINE MODEL

帕金森病 6 羟多巴胺模型

• 批准号: 6696702
• 负责人: Charleen T Chu
• 金额: $ 25.79万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-20 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696702
• 关键词: 6 hydroxydopamine; Parkinson' s disease; autooxidation; biological signal transduction; cell line; confocal scanning microscopy; disease /disorder model; dopamine; dopamine receptor; drug administration rate /duration; enzyme induction /repression; immunocytochemistry; intermolecular interaction; laboratory mouse; mitogen activated protein kinase; neural degeneration; neurochemistry; neuropathology; neuroprotectants; neurotoxins; neurotransmitter metabolism; nitric oxide; oxidative stress; phosphorylation; superoxide dismutase; tyrosine

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.

描述（申请人摘要）：帕金森病是最常见的疾病 老年人口的衰弱性运动障碍。神经元 帕金森病的退化会受到氧化应激的增加 因为多巴胺过程中会产生超氧化物和其他活性物质 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， 它可以有针对性地选择性损害黑质纹状体系统 帕金森病退化。磷酸酪氨酸信号通路 被神经保护因子激活，例如脑源性神经营养因子 和神经胶质细胞源性神经营养因子，对于多巴胺能很重要 神经元功能和存活。本提案旨在调查 假设氧化剂介导的磷酸酪氨酸信号传导改变 导致帕金森病中多巴胺能神经元的退化。 硝基酪氨酸是涉及过氧亚硝酸盐形成的氧化应激标志物， 在 6-OHDA 啮齿动物模型和人类帕金森病大脑中均增加 组织。过氧亚硝酸盐是由超氧化物与硝酸反应形成的 氧化物，表明这些自由基与帕金森病的发病机制有关 疾病。在此提案中，6-OHDA、超氧化物和硝酸的作用机制 将使用以下方法研究氧化物对磷酸酪氨酸信号级联的影响 永生化多巴胺能神经元系和基因改变水平的小鼠 细胞外超氧化物歧化酶。这套全面的研究将 得出有关氧化应激机制的重要见解 影响多巴胺能神经元的神经营养信号传导，可能 有助于联合抗氧化-神经营养因子的发展 帕金森病的治疗方法。

项目成果

Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases.

• DOI: 10.1016/s0002-9440(10)64487-2
• 发表时间: 2002-12
• 期刊: The American journal of pathology
• 作者: Jian‐hui Zhu;S. Kulich;T. Oury;C. Chu