Dopamine Toxicity and Mitochondrial Dysfunction

多巴胺毒性和线粒体功能障碍

• 批准号: 6894807
• 负责人: TERESA G HASTINGS
• 金额: $ 30.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6894807
• 关键词: Parkinson' s disease; adduct; cell death; cell line; chemical conjugate; corpus striatum; cysteine; disease /disorder model; dopamine; free radical oxygen; laboratory rat; mass spectrometry; mitochondria; molecular pathology; neural degeneration; neurotoxins; neurotransmitter metabolism; oxidation; posttranslational modifications; protein purification; quinones; substantia nigra; tissue /cell culture

DESCRIPTION (provided by applicant): This study will focus on the fundamental question of whether reactive metabolites of dopamine, may be contributing to the pathogenesis of neurodegenerative disorders such as Parkinson's disease. Dopamine has been shown to be toxic to cells both in vitro and in vivo. However, the exact mechanism associated with the toxicity is not known. Because mitochondria play a critical role in mechanisms of cell death, the proposed studies are designed to increase our understanding of the interplay between reactive metabolites of dopamine and mitochondrial function, and their ability to enhance the vulnerability of dopaminergic neurons to injury. In Aim 1, we will characterize the temporal relationship between loss of mitochondrial function and cell death following exposure to dopamine. In Aim 2, using striatonigral organotypic cultures, we will examine whether dopaminergic neurons exhibit an increased vulnerability to mitochondrial inhibition and whether dopamine contributes to this effect. Finally, in Aim 3, we will determine the identity of critical proteins modified and inactivated by dopamine quinones using mass spectrometry, with a focus on mitochondrial proteins. The outcome of these studies has potential for identifying new therapeutic targets for stopping and preventing the neurodegenerative process in Parkinson's disease.

描述（由申请人提供）：这项研究将重点介绍多巴胺反应性代谢物是否可能导致神经退行性疾病（如帕金森氏病）的发病机理的基本问题。多巴胺已被证明在体外和体内都对细胞有毒。但是，与毒性相关的确切机制尚不清楚。由于线粒体在细胞死亡机制中起关键作用，因此拟议的研究旨在提高我们对多巴胺反应性代谢产物与线粒体功能之间的相互作用的理解，以及增强多巴胺能神经元脆弱性受伤的能力。在AIM 1中，我们将表征暴露于多巴胺后线粒体功能丧失与细胞死亡之间的时间关系。在AIM 2中，使用纹状体细胞型培养物，我们将检查多巴胺能神经元是否表现出较大的线粒体抑制作用，以及多巴胺是否有助于这种作用。最后，在AIM 3中，我们将确定使用质谱法修饰和灭活的临界蛋白质的身份，重点是线粒体蛋白。这些研究的结果有可能鉴定出停止和防止帕金森氏病的神经退行性过程的新的治疗靶标。