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Defining the roles and regulation of neuronal autophagy

定义神经元自噬的作用和调节

基本信息

批准号：
10348388
负责人：
Sandra L. Maday
金额：
$ 2.54万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348388
关键词：
Affect Age-associated memory impairment Astrocytes Autophagocytosis Autophagosome Axon Biochemistry Biological Models Biology Birth Brain-Derived Neurotrophic Factor Cells Cellular biology Coculture Techniques Complex Cues Data Defect Degradation Pathway Dendrites Disease Distant Electrophysiology (science)Environment Gene Expression Genes Goals Hippocampus (Brain)Homeostasis Human Lead Learning Link Lysosomes Mammals Maps Measures Mediating Memory Metabolism Modeling Molecular Morphology Movement Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuronal Dysfunction Neurons Neurosciences Outcome Pathway interactions Phenotype Play Population Presynaptic Terminals Process Property Regulation Research Role Signal Transduction Starvation Stress Synapses Techniques Testing Therapeutic Therapeutic Intervention Time Translations Vacuole Work aged base cell motility density experimental study improved insight knock-down mTOR inhibition nervous system disorder neuron development neuronal cell body neuronal survival neuroprotection neurotrophic factor polarized cell postsynaptic programs response retrograde transport synaptic function

项目摘要

PROJECT SUMMARY Autophagy is a lysosomal degradation pathway that is critical to maintain neuronal homeostasis and survival. Autophagy sequesters damaged and aged cellular components from the intracellular environment and targets them to lysosomes for destruction. Defective autophagy is linked to neurodevelopmental abnormalities and neurodegeneration in mammals. Further, activating autophagy can rescue models of neurodegeneration and age-related cognitive decline in mice. Little is known, however, about the regulation and functions of autophagy that provide neuroprotection. Much of the work to date elucidating the molecular basis of autophagy has been performed in model systems that lack the morphological complexity of neurons. Further, our research has revealed that several canonical paradigms, including starvation and mTOR-inhibition, that trigger autophagy in non-neuronal cells do not robustly induce autophagy in neurons. Thus, it is critical to study autophagy directly in neurons to provide insight that may improve therapies to mitigate diseases of neuronal dysfunction. Thus, the objective for this proposal is to define the roles and regulation of neuronal autophagy that facilitate neuronal function and survival. We established that autophagy in neurons is a highly compartmentalized process. Axonal autophagy is a unidirectional pathway that allows cargo delivery from distant regions of the axon to the soma for degradation. In contrast to the long-range pathway for autophagy in axons, dendritic autophagy is defined by bidirectional movement of autophagic vacuoles (AVs) that may execute more localized functions. Our preliminary data have identified three aspects of neuronal biology (synaptic connectivity, neurotrophic support, and interactions with astrocytes) that regulate autophagy in specific neuronal compartments. We find that synaptic activity controls AV dynamics selectively in dendrites and not in the axon. We find that the neurotrophin BDNF induces retrograde autophagic flux along axons. Lastly, we find that co- culturing neurons with astrocytes decreases autophagosome density in axons. The mechanistic basis for these pathways and their functions, however, are unknown. Based on our preliminary data, we hypothesize that synaptic activity, neurotrophins, and astrocytes differentially regulate autophagy in neurons, and, that autophagy plays compartment-specific roles in neuronal function and survival. To test this hypothesis, we will pursue three aims: (1) Define how synaptic activity regulates neuronal autophagy and how autophagy affects synapse function; (2) Determine how neurotrophins regulate neuronal autophagy and how autophagy impacts neurotrophin signaling; and (3) Elucidate how neuronal autophagy is regulated by astrocytes. We will use quantitative approaches in cell biology, biochemistry, and electrophysiology to gain a mechanistic understanding for each pathway. These studies will comprehensively map the pathways and functions for autophagy in neurons in response to diverse interactions from their complex environment. New insights gained from this study will better inform strategies for therapeutic intervention to treat disorders of the nervous system.

项目总结