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ROLE OF MIRO SIGNALING FOR AXONAL TRANSPORT OF MITOCHONDRIA

MIRO 信号传导在线粒体轴突运输中的作用

基本信息

批准号：
8653841
负责人：
KONRAD ERNST ZINSMAIER
金额：
$ 31.82万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8653841
关键词：
Affect Autophagocytosis Axon Axonal Transport Binding Biological Models Biology C-terminal Cells Complex Coupled Defect Dendrites Development Disease Distal Docking Drosophila genus Dynein ATPase EF Hand Motifs Ensure Event Exhibits Genetic Goals Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Health ITPR1 gene Impairment Kinesin Link Lipids Maintenance Mediating Membrane Potentials Mitochondria Molecular Motion Motor Mutation N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurons Neuropathy Paraplegia Pathology Pathway interactions Phenotype Protein Isoforms Proteins Residencies Role Signal Transduction Site Structure Synapses Synaptic Transmission System Testing Time Translations Transmembrane Domain anterograde transport genetic analysis insight mutant neuronal cell body neuronal excitability neuronal survival parkin gene/protein prevent response retrograde transport rho scaffold

项目摘要

DESCRIPTION (provided by applicant): Supplying axons, dendrites, and synapses with mitochondria is vital for sustaining neuronal excitability and synaptic transmission. In contrast to most other cells, mitochondrial transport is critical for neuronal survival, as impaired transport causes the same pathology as impaired mitochondrial function. A combination of the large distance between soma and synapses, the complexity of neuronal branches, the need to relocate mitochondria in response to changes in neuronal activity, coupled with the need of mitochondria to eventually return to the cell body requires a transport system that is sensitive to pathways communicating the "energetic state of the neuron" and the "state of the mitochondrion". However, we know little about the link between mitochondrial transport and mechanisms that maintain mitochondrial function in axons. A better understanding is urgently needed because even slight impairments of mitochondrial function and/or distribution can cause or intensify neuropathy, neurodegeneration, and/or paraplegia. The evolutionarily conserved mitochondrial GTPase Miro contains two Ca2+ binding domains sandwiched between Rho- and Rab-like GTPase (G) domains. Our genetic analysis shows that mutations in Miro have pleiotropic effects on the biology of mitochondria in axons. We hypothesize that Miro is a central integration node for multimodal signals that controls distinct mechanisms including mitochondrial transport, mitochondrial fusion & fission and autophagy. To test this further, we are taking advantage of the model system Drosophila to elucidate the multiple roles of Miro in neurons by genetically manipulating Miro and its interacting proteins. Aim 1 will characterize how Miro's G1 domain promotes the use of kinesin for anterograde transport and the use of dynein for retrograde transport in axons. Aim 2 will characterize the Ca2+-sensitive role of Miro for mitochondrial function in axons. Aim 3 will characterize the role of Miro for mitochondrial fusion & fission and/or autophagy. The project is expected to reveal critical insights into molecular signaling mechanisms that ensure mitochondrial function in axons. Uncovering these pathways will expand our understanding of logistical mechanisms that are critical for the long-term survival of neurons.

描述（申请人提供）：为轴突、树突和突触提供线粒体对于维持神经元兴奋性和突触传递至关重要。与大多数其他细胞相比，线粒体运输对神经元存活至关重要，因为运输受损导致的病理与线粒体功能受损相同。胞体和突触之间的大距离，神经元分支的复杂性，需要重新安置线粒体以响应神经元活动的变化，再加上线粒体最终返回细胞体的需要，这些因素结合在一起，需要一个对“神经元的能量状态”和“线粒体状态”之间的沟通途径敏感的运输系统。然而，我们对线粒体运输和维持轴突线粒体功能的机制之间的联系知之甚少。我们迫切需要更好的理解，因为即使线粒体功能和/或分布的轻微损伤也会导致或加剧神经病变、神经变性和/或截瘫。进化保守的线粒体GTPase Miro包含两个Ca2+结合结构域夹在Rho-和rablike GTPase (G)结构域之间。我们的遗传分析表明，Miro突变对轴突线粒体的生物学有多效性影响。我们假设Miro是控制不同机制的多模态信号的中心整合节点，包括线粒体运输、线粒体融合和裂变以及自噬。为了进一步验证这一点，我们利用果蝇模型系统，通过基因操纵Miro及其相互作用蛋白来阐明Miro在神经元中的多重作用。目的1将描述Miro的G1结构域如何促进轴突中使用动力蛋白进行顺行运输和使用动力蛋白进行逆行运输。目的2将表征Ca2+的Miro对轴突线粒体功能的敏感作用。目的3将描述Miro在线粒体融合、裂变和/或自噬中的作用。该项目有望揭示确保轴突线粒体功能的分子信号机制的关键见解。揭示这些通路将扩大我们对神经元长期存活的关键逻辑机制的理解。