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

• 批准号: 10320469
• 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
• 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/10320469
• 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

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神经胶质细胞信号通路如何驱动巨噬细胞吞噬能力， 神经胶质，并定义其功能修剪神经元的数量和连接在整个生命周期。胶质 为健康的神经元提供广泛的支持系统，促进它们的存活，连接， 和突触功能。值得注意的是，神经胶质可以迅速转换角色，精确地消灭垂死的神经元 或通过吞噬作用去除不需要的神经突/突触。这些截然相反的功能需要 神经元和神经胶质之间的安全信号机制;然而， 仍然很模糊。Toll样受体（TLR）途径首先被鉴定为它们在以下中的作用： 胚胎模式，并已被定义为先天免疫的保守的核心。 我们的实验室意外地发现， 果蝇TLR的丧失，在细胞凋亡过程中凋亡神经元数量的急剧增加， 在发育过程中，TLR的选择性丢失是由胶质细胞中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胶质细胞中的新TLR途径以驱动吞噬能力。 在这项提案中，我们建立在我们新的初步发现，以建立这种途径如何调节 碎片清除速度和特异性，并确定其在突触中神经元-神经胶质相互作用中的作用， 神经突和整个生命周期中的神经元移除。我们的统一假设是，非典型TLR 信号传导是碎片清除的速度和特异性的基础，碎片清除对中枢神经系统的正常发育至关重要 和功能在第一个目标中，我们着重于阐明胶质细胞是如何转化为吞噬细胞， 通过定义信息是如何通过TLR途径传递的，以阐明胶质细胞是如何通过TLR途径表达的， 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 调查TLR信号是否是一个广泛的早期检测系统，以提醒胶质细胞的存在 神经元碎片在第三个目标中，我们研究了TLR信号在塑造电路中的作用 基于我们的初步发现，即胶质细胞TLR信号抑制突触， 在这条清晰的线路上。在这里，我们建议利用苍蝇嗅觉回路作为一个模型， 定义神经胶质吞噬细胞在突触维持中的功能。总之，这些研究将摆脱关键的 光的早期信号之间的相互作用神经胶质细胞和他们的吞噬基板必不可少的 整个生命周期的大脑健康。