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.

该提案研究了一种新型 TLR 神经胶质信号通路如何驱动吞噬细胞的能力神经胶质细胞，并定义了其在整个生命周期中修剪神经元数量和连接性的功能。胶质细胞通过促进健康神经元的生存、连接、和突触功能。值得注意的是，神经胶质细胞可以快速转换角色以精确消除垂死的神经元或通过吞噬作用产生不需要的神经突/突触。这些截然相反的功能需要神经元和神经胶质细胞之间的故障安全信号机制；然而这些关键的监管机制很大程度上仍然不为人知。 Toll 样受体 (TLR) 通路最初因其在胚胎模式，并从此被定义为先天免疫的保守核心。我们的实验室意外地发现，与以下因素相关的最显着的表型之一果蝇 TLR 缺失，凋亡神经元数量急剧增加发育是由神经胶质细胞中 TLR 的选择性丢失引起的。我们证明了 TLR 的释放来自垂死神经元的配体激活神经胶质细胞中的一种新型 TLR 通路，以驱动吞噬能力。在本提案中，我们以我们新颖的初步发现为基础，确定该途径如何调节碎片清除的速度和特异性，并定义其在突触神经元-胶质细胞相互作用中的作用，整个生命周期中的神经突和神经元去除。我们的统一假设是非规范 TLR 信号传导是碎片清除速度和特异性的基础，这对于中枢神经系统的正常发育至关重要和功能。第一个目标是阐明神经胶质细胞在吞噬细胞过程中如何转化为吞噬细胞。通过定义信息如何通过 TLR 通路传递来阐明神经胶质细胞如何准备好成为吞噬细胞。在第二个目标中，我们寻求将我们已发表的工作扩展到研究 TLR 信号传导是否是一种广泛的早期检测系统，可提醒神经胶质细胞的存在的神经元碎片。第三个目标是研究 TLR 信号在雕刻电路中的功能根据我们的初步发现，神经胶质 TLR 信号传导限制突触这个定义明确的电路中的数字。在这里，我们建议利用苍蝇嗅觉回路作为模型定义突触维护中的神经胶质吞噬功能。总之，这些研究将揭示关键的揭示神经胶质细胞与其吞噬细胞底物之间的早期信号相互作用整个生命周期的大脑健康。