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Exploring the role dense core vesicle release in glial immunity

探索致密核心囊泡释放在神经胶质免疫中的作用

基本信息

批准号：
10029116
负责人：
Mary Allison Logan
金额：
$ 36.19万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10029116
关键词：
Acute Adult Affect Astrocytes Axon Axotomy Biological Assay Biological Models Brain Calcium Calcium Oscillations Cells Chronic Communication Communities Coupled Cues Data Defect Degenerative Disorder Dense Core Vesicle Drosophila genus Drosophila melanogaster Ensure Event Excision Fluorescence Fluorescent in Situ Hybridization Gelatinase A Gene Expression Gene Expression Profiling Genes Genetic Models Genetic Transcription Immune Immune response Immunity Immunologic Factors Inflammation Injury Innate Immune Response Insulin Label Ligands Messenger RNA Methods Mission Modeling Molecular Monitor Nerve Nerve Degeneration Nervous system structure Neuroglia Neurologic Neurons Neuropeptides Olfactory Pathways Organism Peripheral Phagocytes Play Process Public Health Reaction Recovery Reporter Ribosomal Interaction Role Signal Pathway Signal Transduction Site Stress Synaptic plasticity System Techniques Time Transcript Translating Translations Trauma United States National Institutes of Health Up-Regulation Wallerian Degeneration Wing Work axon injury axonal degeneration brain health cell motility cohort confocal imaging fly genetic manipulation health management high resolution imaging imaging modality immunoreaction in vivo in vivo monitoring insight insulin-like signaling migration molecular subtypes nerve injury nervous system disorder neuroprotection neurotoxic neurotransmission novel programs receptor response single molecule therapy development transcriptome sequencing traumatic event vesicular release

项目摘要

SUMMARY Glial cells play an essential role in defending brain health and managing neuronal stress and damage. Neurodegeneration triggers robust glial immune responses, including changes in cytoskeletal dynamics, glial cell migration, and increased phagocytic activity. Timely removal and degradation of degenerating axons and neuronal debris by glia confers neuroprotection in the brain. Despite the importance of glial responses to axon injury, we still know surprisingly little about how damaged neurons invoke immune reactions in glial cells. What signals are released from degenerating neurons? What prompts the release of these injury cues? Finally, how are these signals translated by glia to carry out efficient immune responses to damage? We are using the fruit fly Drosophila melanogaster as a tractable model to investigate the immune communication relays that exist between neurons and glial cells in vivo. The fly nervous system contains distinct glial subtypes that are molecularly and functionally similar to vertebrate glia. Moreover, well-established axotomy assays in the adult olfactory system and the adult wing reveal that Drosophila axons undergo a classic Wallerian degeneration (WD) program, which includes increased intra-axonal calcium waves, axon fragmentation, and subsequent clearance by phagocytic glia. Notably, our lab has recently shown that axon degeneration triggers activation of the insulin-like signaling (ILS) pathway in reactive ensheathing glia, which, in turn, elicits essential glial immune responses, including transcriptional upregulation of immune genes (e.g. the engulfment receptor Draper) and phagocytic activity. We hypothesize that neuropeptide-containing dense core vesicles (DCVs) are broadly released from severed axons to trigger immune responses in local glial cells. Here, we propose to use static and live confocal imaging, transcriptional profiling, and newly developed in vivo reporters to investigate how neuropeptide signaling between neurons and glia informs glial immune responses to nerve injury. Specifically, we will 1) monitor DCV dynamics and release in adult severed nerves, 2) utilize novel single transcript labeling methods to visualize local translation of immune mRNA transcripts in glial extensions at sites of injury, and 3) determine how neuropeptide signaling between discrete glial subtypes ensures that glial responses to degenerating axons are properly carried out. Together, these findings will offer exciting molecular and cellular insight into how neuropeptide signaling between neurons and glia govern immune responses in both acute and chronic degenerative conditions.

总结