Type I interferon-dependent mechanisms of synapse loss in lupus

狼疮突触丢失的 I 型干扰素依赖性机制

基本信息

  • 批准号:
    10433932
  • 负责人:
  • 金额:
    $ 46.17万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-07-16 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

Abstract Systemic lupus erythematosus is an incurable autoimmune disease characterized by pathogenic autoantibodies that potentiate inflammatory injury in tissues such as skin, lungs and kidneys. Lupus patients also experience neurologic symptoms that range from severe headache and seizures to neuropsychosis and are collectively referred to as CNS Lupus. We propose that neurologic symtoms result from peripheral interferon alpha that enters the brain and activates the microglia and complement -dependent pruning pathway leading to synapse loss in brain regions involved in cognition, spatial memory and social behavior. Studies in murine models of lupus suggest that peripheral immune cells and autoantibody may penetrate the blood brain barrier and induce pathology. However, in lupus patients symptoms of neuropsychosis are often detected early in disease suggesting that other factors might be involved in injury without destruction of the blood brain barrier. In our own study using a murine model of lupus, preliminary results identify an age-dependent significant increase in the frequency of activated microglia that are positive for uptake of neuronal synaptic material. Remarkably, the lupus mice develop changes in behavior that correlate with synapse loss. The pattern of microglia activation and synaptic pruning is similar to that observed during early neural development where selective synapse elimination is normal. Notably, treatment of the lupus mice in vivo with anti-interferon receptor antibody was protective. The objective of this proposal is to test our hypothesis that peripheral cytokines such as type I interferon trigger a microglia-dependent synaptic pruning program leading to increased elimination of synapses that could explain the neurological symptoms observed in lupus. The following two aims are proposed. Specific aim 1: Test the hypothesis that microglia-mediated synaptic pruning becomes activated in SLE. Based on our preliminary data, we predict that microglia-dependent synapse loss occurs in SLE mouse models and that activation of the classical complement cascade is required for this process. Specific aim 2: Test the hypothesis that increased type I interferon signaling in SLE promotes CNS dysfunction We predict that type I interferon-stimulated microglia activate a synapse pruning gene program leading to inappropriate engulfment of neuronal material and development of cognitive and social dysfunction. Moreover, preliminary results suggest that treatment with anti-IFNAR may be protective and prevent synapse loss.
摘要

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Microglial responses to peripheral type 1 interferon.
  • DOI:
    10.1186/s12974-020-02003-z
  • 发表时间:
    2020-11-12
  • 期刊:
  • 影响因子:
    9.3
  • 作者:
    Aw E;Zhang Y;Carroll M
  • 通讯作者:
    Carroll M
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Michael Craig Carroll其他文献

Michael Craig Carroll的其他文献

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{{ truncateString('Michael Craig Carroll', 18)}}的其他基金

Astrocyte-neuron communication and vulnerability to mental illness
星形胶质细胞-神经元通讯和患精神疾病的脆弱性
  • 批准号:
    10686440
  • 财政年份:
    2022
  • 资助金额:
    $ 46.17万
  • 项目类别:
Neuroimmune mechanisms of adolescent brain development and vulnerability
青少年大脑发育和脆弱性的神经免疫机制
  • 批准号:
    10686442
  • 财政年份:
    2022
  • 资助金额:
    $ 46.17万
  • 项目类别:
Contributions of human C4A overexpression to schizophrenia pathogenesis.
人类 C4A 过度表达对精神分裂症发病机制的贡献。
  • 批准号:
    10686441
  • 财政年份:
    2022
  • 资助金额:
    $ 46.17万
  • 项目类别:
Administrative Core (Core A)
行政核心(核心A)
  • 批准号:
    10686439
  • 财政年份:
    2022
  • 资助金额:
    $ 46.17万
  • 项目类别:
Evolution of autoreactive GC and epitope spreading in lupus
狼疮自身反应性GC和表位扩散的演变
  • 批准号:
    10736511
  • 财政年份:
    2018
  • 资助金额:
    $ 46.17万
  • 项目类别:
Evolution of autoreactive GC and epitope spreading in lupus
狼疮自身反应性GC和表位扩散的演变
  • 批准号:
    10399632
  • 财政年份:
    2018
  • 资助金额:
    $ 46.17万
  • 项目类别:
Type I interferon-dependent mechanisms of synapse loss in lupus
狼疮突触丢失的 I 型干扰素依赖性机制
  • 批准号:
    10196940
  • 财政年份:
    2018
  • 资助金额:
    $ 46.17万
  • 项目类别:
Project-004
项目-004
  • 批准号:
    10686445
  • 财政年份:
    2017
  • 资助金额:
    $ 46.17万
  • 项目类别:
Neural-immune mechanisms and synaptic connectivity in psychiatric illness
精神疾病中的神经免疫机制和突触连接
  • 批准号:
    9280281
  • 财政年份:
    2017
  • 资助金额:
    $ 46.17万
  • 项目类别:
Astrocyte-neuron communication and vulnerability to mental illness
星形胶质细胞-神经元通讯和患精神疾病的脆弱性
  • 批准号:
    10693115
  • 财政年份:
    2017
  • 资助金额:
    $ 46.17万
  • 项目类别:
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