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的研究培训计划和研究策略，旨在支持主要研究者发展成为一个独立的神经科学家。该提案的目标是了解缺陷的线粒体运动和功能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。神经元对线粒体功能障碍敏感，因为它们具有高ATP需求并且是极化细胞。在神经元中，线粒体通过线粒体外膜蛋白Miro在轴突内朝向突触末端（顺行）或细胞体（逆行）移动和重新分布。目前的数据表明，顺行线粒体运动提供ATP的突触释放，逆行线粒体运动是重要的细胞器清除。然而，线粒体运动的方向是如何确定的，以及运动与神经元线粒体代谢之间的关系尚不清楚。为了更好地理解这些事件以及它们如何与神经退行性疾病相关，我们将破坏Miro介导的线粒体运动，并确定对线粒体功能、神经元中的线粒体分布和神经退行性疾病的影响。使用由申请人产生的Miro1 KO小鼠和定量荧光显微镜方法，我们将确定轴突中的线粒体顺行和逆行运动。我们还将通过测量线粒体膜电位和线粒体基因组丢失来评估线粒体稳态。最后，我们将通过神经系统检查、神经切片和代谢表型分析方法，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。公共卫生相关性：了解神经元中线粒体运动的分子调控以及这些运动与线粒体功能之间的关系对于开发新的治疗干预措施来治疗由线粒体功能障碍引起的神经退行性疾病非常重要。除了拟议的研究外，还在神经退行性疾病和线粒体生物学专家的指导下概述了定制的培训计划。 公共卫生相关性： 关于神经退行性疾病的发病机制的一些重要问题仍然没有答案。首先，轴突线粒体运动的中断会恶化神经元功能吗？第二，线粒体运动对线粒体呼吸功能至关重要吗？第三，米罗功能障碍是否改变了哺乳动物的线粒体分布并导致神经退行性变？如果成功，这些研究将有助于更好地了解与线粒体功能障碍相关的神经变性，并可能为治疗干预提供见解。因此，我们觉得这个建议有很强的动起来的可能性 场向前。

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. PUBLIC HEALTH RELEVANCE: Understanding the molecular regulation of mitochondrial movements in neurons and the relationship between those movements and mitochondrial function is important for developing new therapeutic interventions to treat neurodegenerative disease caused by mitochondrial dysfunction. In addition to the proposed research, a customized training plan is outlined under the mentorship of experts in neurodegenerative diseases and mitochondrial biology. PUBLIC HEALTH RELEVANCE: A number of important questions regarding the pathogenesis of neurodegenerative diseases remain unanswered. First, does disruption of axonal mitochondrial movement deteriorate neuron function? Second, is mitochondrial movement essential for mitochondrial respiratory function? Third, does Miro dysfunction alter mitochondrial distribution and lead neurodegeneration in mammals? If successful, these studies will lead to a better understanding of neurodegeneration related to mitochondrial dysfunction and possibly offer insight towards therapeutic interventions. Therefore, we feel that this proposal has a strong possibility of moving the field forward.