Mitochondral Function in Neurodegeneration

神经退行性变中的线粒体功能

• 批准号: 6609653
• 负责人: IAN J REYNOLDS
• 金额: $ 17.69万
• 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: 2002-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6609653
• 关键词: Parkinson's disease; astrocytes; cell component structure /function; cell line; cytoskeleton; dopamine; imaging /visualization /scanning; mitochondria; neural degeneration; neurons; neurotoxicology; substantia nigra; technology /technique development; tissue /cell culture; Parkinson's disease; astrocytes; cell component structure /function; cell line; cytoskeleton; dopamine; imaging /visualization /scanning; mitochondria; neural degeneration; neurons; neurotoxicology; substantia nigra; technology /technique development; tissue /cell culture

DESCRIPTION (provided by applicant): Recent studies have illuminated an important role for mitochondria in the expression of injury mediated by a number of distinct neurotoxic mechanisms. This suggests that the study of both the normal and pathophysiological function of mitochondria is critical in the investigation of neurodegenerative mechanisms. The long-term aim of this project is to identify the mechanisms by which mitochondria contribute to neuronal injury, and to use this understanding to design novel neuroprotective approaches. We will undertake four aims in this project that are designed to characterize a newly recognized phenomenon of spontaneous mitochondrial changes (SMC's) in cultures of neurons, astrocytes and HT22 cells. We believe that these changes provide a valuable window into mitochondrial function in normal neural cells. However, the mechanistic basis for SMC's is completely unknown. In aim 1 we will determine whether mitochondrial movement contributes to SMC's and develop novel imaging approaches to measure relevant phenomena. In specific aims 2 and 3, using SMD's as a marker we will investigate the mechanisms underlying SMC's using manipulations that alter both physiological and pathophysiological parameters. Finally, in specific aim 4 we will establish an organotypic culture model of the degeneration of nigral neurons in Parkinson's disease (PD) using approaches that allow us to identify dopaminergic neurons prior to performing imaging experiments. We will then assess mitochondrial function in dopaminergic neurons exposed to toxins that produce lesions specific to nigral dopaminergic neurons. This project will provide new insights into several critical aspects of mitochondrial function in neurons and astrocytes that will illuminate their role in normal cell physiology as well as in neurodegeneration and will direct future studies that develop novel approaches for intervention in a range of acute and chronic neurodegenerative diseases.

描述（由申请人提供）：最近的研究阐明了线粒体在许多不同的神经毒性机制介导的损伤表达中的重要作用。这表明对线粒体的正常生理功能的研究对于研究神经退行性机制至关重要。该项目的长期目的是确定线粒体会导致神经元损伤的机制，并利用这种理解来设计新型的神经保护方法。我们将在该项目中实现四个目标，这些目标旨在表征神经元，星形胶质细胞和HT22细胞培养物中自发性线粒体变化（SMC）的新现象。我们认为，这些变化为正常神经细胞中线粒体功能提供了有价值的窗口。但是，SMC的机械基础是完全未知的。在AIM 1中，我们将确定线粒体运动是否有助于SMC的运动并开发出新颖的成像方法来衡量相关现象。在特定的目标2和3中，使用SMD作为标记，我们将使用改变生理和病理生理参数的操纵来研究SMC的基础机制。最后，在特定的目标4中，我们将使用允许我们在进行成像实验之前鉴定多巴胺能神经元的方法建立一个细胞型培养模型（PD）在帕金森氏病（PD）中的变性模型。然后，我们将评估暴露于产生特定于ni骨多巴胺能神经元病变的毒素的多巴胺能神经元中的线粒体功能。该项目将为神经元和星形胶质细胞中线粒体功能的几个关键方面提供新的见解，这些方面将阐明其在正常细胞生理学以及神经分发中的作用，并将指导未来的研究，以开发出一系列急性急性和慢性神经退行性疾病的新方法。