Mitochondrial oxidative damage in dopaminergic cells

多巴胺能细胞线粒体氧化损伤

• 批准号: 6910777
• 负责人: Enrique Cadenas
• 金额: $ 40.63万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-11 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6910777
• 关键词: Parkinson' s disease; cell death; dopamine; free radical oxygen; glutathione; laboratory rat; mitochondria; nitric oxide; nitric oxide synthase; oxidative stress; pathologic process; superoxide dismutase

Long-term goal. The long-term goal of the proposed study is to understand the role of mitochondria and oxidative stress in the dopaminergic cell death, associated with the Parkinson's disease. Hypothesis. The hypothesis to be tested is that (a) an increase in the steady-state levels of nitric oxide stimulates both dopamine autoxidation and mitochondrial oxidant production; (b) the ensuing increase in the oxidative load of the dopaminergic cell leads to specific mitochondrial dysfunctions. Specific Aims. The testing of the biochemical pathway envisioned by this hypothesis will constitute the specific aims of this study, which include: (1) Determine how nitric oxide regulates autoxidation of dopamine, a process which generates reactive oxygen species and nitrogen-centered oxidants. (2) Determine the effects of nitric oxide and dopamine on mitochondrial functional integrity in intact cells. (3) Identify the mitochondrial proteins that become oxidized by reactive species derived from dopamine autoxidation. (4) Explore the mechanisms by which oxidative/nitrosative damage to mitochondria may be attenuated. Collectively, these studies will attempt to scrutinize the plausibility of a biochemical model explaining the deleterious alterations occurring during Parkinson's disease. Significance. Specifically, the results in this study will help elucidate the mechanisms by which nitric oxide induces autoxidation of dopamine and leads to the impairment of mitochondrial functions. Understanding of the nature of the putative mechanisms is deemed to be an indispensable step in developing therapeutic interventions.

长期目标。 拟议的研究的长期目标是了解与帕金森氏病有关的线粒体和氧化应激在多巴胺能细胞死亡中的作用。假设。 要测试的假设是（a）一氧化氮稳态水平的增加刺激了多巴胺自氧化和线粒体氧化剂的产生； （b）多巴胺能细胞的氧化负荷随之增加导致特定的线粒体功能障碍。具体目标。 该假设所设想的生化途径的测试将构成本研究的具体目的，其中包括：（1）确定一氧化氮如何调节多巴胺的自氧化，这一过程产生了活性氧和氮气中的氧化剂。 （2）确定一氧化氮和多巴胺对完整细胞中线粒体功能完整性的影响。 （3）确定通过多巴胺自氧化的反应性物种氧化的线粒体蛋白。 （4）探讨可能减弱对线粒体氧化/亚硝化损伤的机制。总的来说，这些研究将试图审查生化模型的合理性，以解释帕金森氏病期间发生的有害变化。意义。具体而言，这项研究的结果将有助于阐明一氧化氮诱导多巴胺自氧化并导致线粒体功能受损的机制。 理解推定机制的性质被认为是制定治疗干预措施的必不可少的一步。