Relationship Between Miro GTPase Directed Mitochondrial Movement & Neurodegenerat

描述（由申请人提供）：该提案描述了一个博士前研究培训计划和研究策略，旨在支持首席研究员发展成为一个独立的神经科学家。本提案的目的是了解线粒体运动和功能缺陷如何导致神经退行性疾病。几乎所有的神经退行性疾病都涉及线粒体分布缺陷和呼吸功能障碍。神经元易受线粒体功能障碍的影响，因为它们需要高ATP并且是极化细胞。在神经元中，线粒体通过外线粒体膜蛋白Miro在轴突内向突触末端（顺行）或细胞体（逆行）移动和重新分布。目前的数据表明，线粒体顺行运动为突触释放提供ATP，线粒体逆行运动对细胞器清除很重要。然而，线粒体运动方向是如何确定的，以及运动与神经元线粒体代谢之间的关系尚不清楚。为了更好地了解这些事件及其与神经退行性疾病的关系，我们将破坏Miro介导的线粒体运动，并确定对线粒体功能、神经元中线粒体分布和神经退行性疾病的影响。使用申请人生成的Miro1 KO小鼠和定量荧光显微镜方法，我们将确定线粒体轴突的顺行和逆行运动。我们还将通过测量线粒体膜电位和线粒体基因组损失来评估线粒体稳态。最后，我们将通过神经学检查、神经切片和代谢表型方法评估在整个动物发育过程中破坏线粒体运动的神经和代谢后果。

DESCRIPTION (provided by applicant): This proposal describes a pre-doctoral research-training plan and research strategy designed to support the principal investigator's development into an independent neuroscientist. The goal of this proposal is to understand how defective mitochondrial movement and function contribute to neurodegenerative diseases. Nearly all neurodegenerative diseases involve mitochondrial distribution defects and respiratory dysfunction. Neurons are susceptible to mitochondrial dysfunction because they have high ATP demands and are polarized cells. In neurons, mitochondria are moved and redistributed within the axon towards either the synaptic terminal (anterograde) or to the cell body (retrograde) by an outer mitochondrial membrane protein, Miro. Current data suggest that anterograde mitochondrial movement supplies ATP for synaptic release, and retrograde mitochondrial movement is important for organelle clearance. However, how the direction of mitochondrial movement is determined and the relationship between movement and mitochondrial metabolism in neurons is unclear. To better understand these events and how they relate to neurodegenerative diseases, we will disrupt Miro- mediated mitochondrial movement and determine the effect on mitochondrial function, mitochondrial distribution in neurons and neurodegeneration. Using Miro1 KO mice generated by the applicant and quantitative fluorescence microscopy methods, we will determine mitochondrial anterograde and retrograde movements in axons. We will also assess mitochondrial homeostasis by measuring mitochondrial membrane potential and mitochondrial genome loss. Finally, we will evaluate the neurological and metabolic consequence of disrupting mitochondrial movement throughout development in whole animals by neurological exams, neural sectioning and metabolic phenotyping methods.