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.

这项建议研究了一条新的TLR神经胶质信号通路如何驱动巨噬细胞吞噬能力 Glia，并定义了它在修剪神经元数量和跨寿命连接方面的功能。神经胶质细胞 通过促进神经元的存活、连接，为健康的神经元提供广泛的支持系统 和突触功能。值得注意的是，胶质细胞可以迅速转换角色，精确地消除死亡的神经元 或通过吞噬作用形成不需要的轴突/突触。这些截然相反的功能必然 神经元和神经胶质细胞之间的故障保护信号机制；但这些关键的调节机制 在很大程度上仍然鲜为人知。Toll样受体(TLR)通路首次被确定为它们在 胚胎模式，自那以后被定义为一种保守的先天免疫中心。 我们的实验室出人意料地发现，最显著的表型之一与 失去一只果蝇TLR，凋亡神经元数量急剧增加 发育，是由胶质细胞中TLR的选择性丢失引起的。我们演示了TLR的发布 来自死亡神经元的配体激活了胶质细胞中一条新的TLR途径，以驱动吞噬能力。 在这个提案中，我们建立在我们的新的初步发现的基础上，以确定这一途径如何调节 碎片清除的速度和特异性，并确定其在突触中神经元-神经胶质细胞相互作用中的作用， 神经突起，以及在整个生命周期内移除神经元。我们的统一假设是非正则TLR 信号是碎片清除的速度和特异性的基础，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，我们专注于阐明胶质细胞是如何转化为吞噬细胞的。 通过定义信息如何通过TLR途径传递来阐明胶质细胞如何 已经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信号是否是一种广泛的早期检测系统，以提醒神经胶质细胞的存在 神经元碎片。在第三个目标中，我们研究了TLR信号在造型电路中的作用 在嗅觉系统中，基于我们的初步发现，胶质TLR信号抑制突触 在这个定义良好的电路中的数字。在这里，我们建议利用苍蝇嗅觉电路作为 明确突触维持中的胶质细胞吞噬功能。总而言之，这些研究将使关键 胶质细胞与其吞噬底物之间的早期信号相互作用 整个生命周期的大脑健康。