Relationship Between Miro GTPase Directed Mitochondrial Movement & Neurodegenerat

描述(由申请人提供)：本提案描述了一项博士前研究培训计划和研究战略，旨在支持首席研究员发展成为独立的神经科学家。这项建议的目标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。神经元容易受到线粒体功能障碍的影响，因为它们对三磷酸腺苷的需求很高，而且是极化细胞。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了ATP，而逆行线粒体运动对细胞器的清除是重要的。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。为了更好地了解这些事件及其与神经退行性疾病的关系，我们将干扰Miro介导的线粒体运动，并确定其对线粒体功能、线粒体在神经元中的分布和神经退行性变的影响。利用申请者培育的Miro1 KO小鼠和定量荧光显微镜方法，我们将测定轴突中线粒体的顺行和逆行运动。我们还将通过测量线粒体膜电位和线粒体基因组丢失来评估线粒体的动态平衡。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整个动物发育过程中线粒体运动中断的神经学和代谢后果。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，在神经退行性疾病和线粒体生物学专家的指导下，还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发病机制的一些重要问题仍未得到解答。首先，轴突线粒体运动的中断是否会恶化神经元的功能？第二，线粒体运动对线粒体呼吸功能是必需的吗？第三，Miro功能障碍是否会改变哺乳动物的线粒体分布并导致神经变性？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退行性变，并可能为治疗干预提供见解。因此，我们觉得这项建议具有很强的移动性。 前场前锋。

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.