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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：
9272960
负责人：
Marc R Freeman
金额：
$ 19.25万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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：
2016-09-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272960
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 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 Neurologic Symptoms Neurons Oxidation-Reduction Oxidative Stress PINK1 gene Parkinson Disease Pathway interactions Patients Phenotype Physiology Play Population Process Production Research Resolution Role Speed Structure Sum Superoxides System Techniques Toxin Width Work 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 superoxide dismutase 1 tool

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.

摘要