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Retooling innate immunity: An investigation of TLR-mediated glial priming across lifespan

重组先天免疫：跨生命周期 TLR 介导的神经胶质启动的研究

基本信息

批准号：
10533785
负责人：
Heather Broihier
金额：
$ 40.25万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10533785
关键词：
Adult Affinity Apoptosis Apoptotic Automobile Driving Cells Clinical Communication Competence Consumption Development Disease Drosophila genus Early Diagnosis Embryo Ensure Excision Foundations Human Inflammation Innate Immune System Investigation Ligands Link Longevity MAP Kinase Gene Maintenance Mediating Mental disorders Modeling Molecular Natural Immunity Necrosis Nervous System Neurites Neurodevelopmental Disorder Neuroglia Neurons Olfactory Pathways Pathway interactions Pattern Phagocytes Phagocytosis Phenotype Play Population Presynaptic Terminals Process Publishing Receptor Signaling Research Role Rupture Shapes Signal Pathway Signal Transduction Specificity Speed Stereotyping Support System Synapses System TXN gene Testing Toll-Like Receptor Pathway Toll-like receptors Work axon guidance axon injury brain health density detection platform fly in vivo Model insight interest neural circuit neurodevelopment neuron loss neurotransmission novel presynaptic prevent receptor spatiotemporal success synaptic function synaptogenesis tool virtual

项目摘要

This proposal examines how a novel TLR glial signaling pathway drives phagocytic competence in glia, and defines its function in pruning neuronal number and connectivity across lifespan. Glia provide an extensive support system for healthy neurons by promoting their survival, connectivity, and synaptic function. Remarkably, glia can rapidly switch roles to precisely eliminate dying neurons or unwanted neurites/synapses by phagocytosis. These diametrically opposed functions necessitate fail-safe signaling mechanisms between neurons and glia; yet hese crucial regulatory mechanisms have remained largely obscure. Toll-like receptor (TLR) pathways were first identified for their roles in embryonic patterning and have since been defined as a conserved centerpiece of innate immunity. Our lab made the unexpected discovery that one of the most pronounced phenotypes associated with loss of a Drosophila TLR, a dramatic increase in the number of apoptotic neurons during development, is caused by selective loss of the TLR in glia. We demonstrated that release of the TLR ligand from dying neurons activates a novel TLR pathway in glia to drive phagocytic competence. In this proposal we build on our novel preliminary findings to establish how this pathway regulates the speed and specificity of debris clearance, and define its roles in neuron-glia interactions in synapse, neurite, and neuron removal across lifespan. Our unifying hypothesis is that non-canonical TLR signaling underlies the speed and specificity of debris clearance critical for proper CNS development and function. In the first aim, we focus on elucidating how glia are transformed into phagocytes during development by defining how information is relayed through the TLR pathway to elucidate how glia are primed to become phagocytic. In the second aim, we seek to extend our published work to investigate whether TLR signaling is a widespread early detection system to alert glia to the presence of neuronal debris. And in the third aim, we examine the function of TLR signaling in sculpting circuits in the olfactory system based on our preliminary findings that glial TLR signaling constrains synapse number in this well defined circuit. Here we propose to leverage the fly olfactory circuit as a model for defining glial phagocytic function in synapse maintenance. Together, these studies will shed critical light on the early signaling interactions between glia and their phagocytic substrates essential for brain health across lifespan.

本研究探讨了一种新的TLR胶质信号通路如何驱动细胞吞噬能力