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:
    10320469
  • 负责人:
  • 金额:
    $ 40.25万
  • 依托单位:
  • 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

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

项目成果

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Heather Broihier其他文献

Heather Broihier的其他文献

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{{ truncateString('Heather Broihier', 18)}}的其他基金

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:
    10533785
  • 财政年份:
    2021
  • 资助金额:
    $ 40.25万
  • 项目类别:
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:
    10154172
  • 财政年份:
    2021
  • 资助金额:
    $ 40.25万
  • 项目类别:
Linking an activity-dependent BMP pathway to synapse structure and function
将活动依赖性 BMP 通路与突触结构和功能联系起来
  • 批准号:
    10606602
  • 财政年份:
    2016
  • 资助金额:
    $ 40.25万
  • 项目类别:
Linking an activity-dependent BMP pathway to synapse structure and function
将活动依赖性 BMP 通路与突触结构和功能联系起来
  • 批准号:
    9078715
  • 财政年份:
    2016
  • 资助金额:
    $ 40.25万
  • 项目类别:
Linking an activity-dependent BMP pathway to synapse structure and function
将活动依赖性 BMP 通路与突触结构和功能联系起来
  • 批准号:
    10378093
  • 财政年份:
    2016
  • 资助金额:
    $ 40.25万
  • 项目类别:
Establishing a transcriptional pathway for cell-fate and synaptic plasticity
建立细胞命运和突触可塑性的转录途径
  • 批准号:
    8815445
  • 财政年份:
    2014
  • 资助金额:
    $ 40.25万
  • 项目类别:
Mechanistic analysis of activity-dependent BMP/TGF-beta release at a model synaps
模型突触活性依赖性 BMP/TGF-β 释放的机制分析
  • 批准号:
    8569373
  • 财政年份:
    2013
  • 资助金额:
    $ 40.25万
  • 项目类别:
Mechanistic analysis of activity-dependent BMP/TGF-beta release at a model synaps
模型突触活性依赖性 BMP/TGF-β 释放的机制分析
  • 批准号:
    8657126
  • 财政年份:
    2013
  • 资助金额:
    $ 40.25万
  • 项目类别:
Linking motorneuron fate and connectivity in Drosophila
连接果蝇运动神经元的命运和连接
  • 批准号:
    7779973
  • 财政年份:
    2006
  • 资助金额:
    $ 40.25万
  • 项目类别:
Linking motorneuron fate and connectivity in Drosophila
连接果蝇运动神经元的命运和连接
  • 批准号:
    7869529
  • 财政年份:
    2006
  • 资助金额:
    $ 40.25万
  • 项目类别:

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