THE PARKINSONIAN 6 HYDROXYDOPAMINE MODEL

帕金森病 6 羟多巴胺模型

• 批准号: 6629343
• 负责人: Charleen T Chu
• 金额: $ 25.88万
• 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 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629343
• 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