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：
10154172
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/10154172
关键词：
Adult 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 Light Link Longevity MAP Kinase Gene Maintenance Mediating Mental disorders Modeling Molecular Natural Immunity Necrosis Nervous system structure Neurites Neurodevelopmental Disorder Neuroglia Neurons Olfactory Pathways Pathway interactions Pattern Phagocytes Phagocytosis Phenotype Play Population Presynaptic Terminals Process Publishing Receptor Signaling 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 base 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 systems research 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.

该建议研究了新型TLR神经胶质信号通路如何驱动吞噬能力神经胶质，并定义了其在整个生命周期中修剪神经元数和连通性方面的功能。神经胶质通过促进其生存，连通性，和突触功能。值得注意的是，神经胶质可以迅速切换到精确消除垂死的神经元或通过吞噬作用不良的神经突/突触。这些截然相反的功能是必要的神经元和神经胶质之间的故障安全信号传导机制；然而至关重要的调节机制在很大程度上保持晦涩难懂。首先确定了Toll样受体（TLR）途径的作用胚胎构图，此后被定义为先天免疫的保守核心。我们的实验室意外发现，与之相关的最明显表型之一果蝇TLR的丧失，凋亡神经元数量的急剧增加开发是由Glia中TLR的选择性丢失引起的。我们证明了TLR的释放垂死神经元的配体激活了胶质细胞中的新型TLR途径，以促进吞噬能力。在这项建议中，我们以新颖的初步发现为基础，以确定该途径如何调节碎片清除的速度和特异性，并定义其在突触中的神经元相互作用中的作用，神经突和神经元在整个寿命中的去除。我们统一的假设是非典型的TLR 信号传导是碎片清除的速度和特异性是适当的中枢神经系统开发至关重要的和功能。在第一个目标中，我们专注于阐明神经胶质在期间如何转化为吞噬细胞通过定义如何通过TLR途径中继信息来开发开发，以阐明神经胶质被启发为吞噬细胞。在第二个目标中，我们试图将发表的工作扩展到调查TLR信号传导是否是一种广泛的早期检测系统，以提醒神经胶质神经元碎片。在第三个目标中，我们检查了TLR信号在雕刻电路中的功能在基于我们的初步发现的嗅觉系统中，神经胶质TLR信号限制了突触这个定义明确的电路中的数字。在这里，我们建议利用飞行嗅觉作为模型在维持突触维持中定义神经胶质细胞功能。这些研究在一起将使至关重要对胶质细胞及其吞噬底物之间的早期信号传导相互作用的光明跨越寿命的大脑健康。