Characterizing new genes that govern mitochondrial function in the axon

表征控制轴突线粒体功能的新基因

基本信息

批准号：
9168491
负责人：
Marc R Freeman
金额：
--
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9168491
关键词：
Affect Amyotrophic Lateral Sclerosis Architecture Area Axon Back Biogenesis Biological Assay Biology Brain Candidate Disease Gene Cells Complex Cytoskeleton Defect Disease Disease Progression Disease model Drosophila genome Drosophila genus Functional disorder Genes Genetic Genetic Screening Health Housing Human Image In Vitro Knowledge Lead Length Life Maintenance Mammals Measures Membrane Potentials Metabolism Mitochondria Morphology Motor Neurons Movement Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurologic Neurons Oxidation-Reduction Oxidative Stress PINK1 gene Parkinson Disease Pathway interactions Patients Phenotype Physiology Play Population Process Production Research Resolution Role Speed Staging Structure Sum Superoxides Symptoms System Techniques Toxin Width Work abstracting base cell motility dopaminergic neuron gene function genome-wide in vivo knock-down meter mitochondrial dysfunction mutant nervous system disorder neuronal cell body novel overexpression parkin gene/protein screening small hairpin RNA tool

Affect Amyotrophic Lateral Sclerosis Architecture Area Axon Back Biogenesis Biological Assay Biology Brain Candidate Disease Gene Cells Complex Cytoskeleton Defect Disease Disease Progression Disease model Drosophila genome Drosophila genus Functional disorder Genes Genetic Genetic Screening Health Housing Human Image In Vitro Knowledge Lead Length Life Maintenance Mammals Measures Membrane Potentials Metabolism Mitochondria Morphology Motor Neurons Movement Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurologic Neurons Oxidation-Reduction Oxidative Stress PINK1 gene Parkinson Disease Pathway interactions Patients Phenotype Physiology Play Population Process Production Research Resolution Role Speed Staging Structure Sum Superoxides Symptoms System Techniques Toxin Width Work abstracting base cell motility dopaminergic neuron gene function genome-wide in vivo knock-down meter mitochondrial dysfunction mutant nervous system disorder neuronal cell body novel overexpression parkin gene/protein screening small hairpin RNA tool

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项目摘要

Abstract Mitochondria are integral to neuronal health. Subsequently, deficits in mitochondrial function contribute to a wealth of neurodegenerative diseases, where axonal dysfunction and die back usually precedes cell body demise. However, we know relatively little about the basic biology of mitochondrial biogenesis, morphological changes, transport, or function in axons in vivo. The discovery and characterization of new molecules regulating fundamental aspects of mitochondrial biology in axons may `open the door' to entirely new lines of research in neurodegenerative disease. In this proposal we aim to discover new regulators of mitochondria function in the axon using a novel and high throughput unbiased forward genetic screening approach recently developed in the lab. This approach allows us to assay mitochondrial morphology, number, and distribution in axons with unprecedented single axon and single mitochondrion resolution in vivo. Newly identified mitochondrial genes will then be characterized using an array of new tools we have optimized for mitochondrial studies in Drosophila, and we will determine precisely how mitochondrial physiology has been altered in vivo. We will also genetically determine how novel mitochondrial regulating genes function in defined pathways to control mitochondrial maintenance. Given that mitochondrial health and function is tightly correlated with neurodegenerative disease, it is likely that a number of these genes will play causal and/or accessory roles in neurodegeneration. We will therefore also investigate whether these novel mitochondria associated molecules have an exacerbated phenotype in dopamine neurons, since they selectively degenerate in Parkinson's disease (PD), a condition where mitochondrial dysfunction and oxidative stress is thought to play a fundamental role in disease progression. Functional conservation of these new molecules will then be assayed in mammalian neurons in vitro. This effort represents (to the best of our knowledge) the first high through forward genetic screen for molecules required for mitochondrial transport to and maintenance in axons. Thus a wealth of novel regulators of neuronal mitochondria, which have potential roles in neurological disease, await identification.

抽象的线粒体是神经元健康不可或缺的。随后，线粒体功能的缺陷有助于神经退行性疾病的财富，轴突功能障碍和后背死亡通常先于细胞体灭亡。但是，我们对线粒体生物发生的基本生物学相对较少了解，体内轴突中的形态变化，运输或功能。新的发现和特征轴突中线粒体生物学的基本方面调节的分子可能“打开门” 神经退行性疾病的新研究。在此提案中，我们旨在发现线粒体在轴突中使用新颖且高吞吐量的无偏向前进遗传筛选最近在实验室开发的方法。这种方法使我们能够测定线粒体形态，数字，以及具有前所未有的单轴和单线粒体分辨率的轴突中的分布体内。然后，新鉴定的线粒体基因将使用我们拥有的一系列新工具来表征针对果蝇的线粒体研究优化，我们将确定线粒体如何确定生理学已在体内改变。我们还将在基因上确定新型线粒体调节基因在控制线粒体维持的定义途径中的功能。鉴于线粒体健康功能与神经退行性疾病紧密相关，可能许多基因将在神经变性中扮演因果和/或附属角色。因此，我们还将调查是否这些新型线粒体相关的分子在多巴胺神经元中具有恶化的表型，由于它们在帕金森氏病（PD）中有选择地退化，这种情况有线粒体功能障碍氧化应激被认为在疾病进展中起着基本作用。功能保护然后，将在体外在哺乳动物神经元中测定这些新分子中的。这项努力代表（对最好的知识）第一个通过前向遗传筛选的高度筛选分子所需的分子线粒体运输到轴突中的维护。因此，神经元的大量新型调节剂线粒体在神经疾病中具有潜在作用，等待鉴定。