Mitochondral Function in Neurodegeneration

描述（由申请人提供）：最近的研究已经阐明了线粒体在由许多不同的神经毒性机制介导的损伤表达中的重要作用。这表明研究线粒体的正常和病理生理功能在神经退行性机制的研究中至关重要。该项目的长期目标是确定线粒体导致神经元损伤的机制，并利用这种理解来设计新的神经保护方法。我们将承担四个目标，在这个项目中，旨在表征一个新认识的现象，自发的线粒体变化（SMC的）在培养的神经元，星形胶质细胞和HT22细胞。我们相信这些变化为正常神经细胞中线粒体功能提供了一个有价值的窗口。然而，SMC的机制基础是完全未知的。在目标1中，我们将确定线粒体运动是否有助于SMC，并开发新的成像方法来测量相关现象。在具体目标2和3中，使用SMD作为标记物，我们将使用改变生理和病理生理参数的操作来研究SMC的潜在机制。最后，在具体目标4中，我们将建立帕金森病（PD）中黑质神经元变性的器官型培养模型，使用允许我们在进行成像实验之前识别多巴胺能神经元的方法。然后，我们将评估暴露于产生黑质多巴胺能神经元特异性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，这些方面将阐明它们在正常细胞生理学和神经退行性疾病中的作用，并将指导未来的研究，开发新的干预方法。

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.