Targeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimer’s disease

靶向 miR-155 和 APOE-TREM2 通路以恢复阿尔茨海默病中功能失调的小胶质细胞

基本信息

  • 批准号:
    9219386
  • 负责人:
  • 金额:
    $ 82.86万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-08-15 至 2022-04-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Alzheimer's disease (AD) is the most prevalent senile dementia affecting 4.5 million Americans. Neuroinflammatory changes are prominent and may significantly contribute to the pathologic process. Mononuclear phagocytes (brain resident microglia and recruited peripheral monocytes) accumulate around amyloid plaque in AD brains. However, their exact cellular identity, molecular and functional phenotypes, and their protective or destructive roles in AD are not well understood. This stems in part from the lack of a specific molecular signatures for mononuclear phagocytes, cell type-specific antibodies, and analytic tools for in situ characterization. We identified that a specific microRNA, miR-155, plays a key role in pro-inflammatory activation of microglia, whereas the TREM2/apolipoprotein E (APOE) axis plays a central role to suppress homeostatic M0 microglia. This may lead to impaired amyloid-β peptide clearance and acceleration of neurodegeneration. Thus, the balance between TREM2 and MERTK expression determines the microglial inflammatory response to apoptotic cells. Restoration of the homeostatic microglia by targeting the specific MERTK pathway represents a novel immunotherapeutic approach. Our preliminary data demonstrate that these novel molecular targets (miR-155, APOE, TREM2 and MERTK) are highly connected biological molecular regulators of microglial phenotypes and thus we will investigate each of these targets to determine their roles in AD. We hypothesize that danger signals (dead neurons and amyloid-β peptides) alter functional phenotype of innate immune cells from the homeostatic (M0) to newly discovered neurodegenerative (MGnD) phenotype. We will address our hypothesis in the following aims: Aim 1: Targeting Trem2-induced Apoe/miR155 pathway to restore M0-homeostatic microglia in AD mouse models. We will specifically delete miR-155, Apoe and Trem2 in microglia of AD mouse models. Aim 2: Restoration of M0-homeostatic microglia via Mertk pathway in humanized APOE4 and AD mice. We will specifically over-express Mertk in microglia of APOE4 humanized mice and AD mouse models. We will validate our findings by investigating AD brains from prodromal to advanced stages. The goal of our investigations is to define new molecular mechanisms of immune and inflammatory processes that contribute to the development and progression of AD, which in turn will provide a basis for new approaches for immune based therapy of the disease.
项目总结

项目成果

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Oleg Butovsky其他文献

Oleg Butovsky的其他文献

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{{ truncateString('Oleg Butovsky', 18)}}的其他基金

Role of a novel risk loci HAVCR2 of late-onset Alzheimer's disease in the regulation of microglial response in neurodegeneration
迟发性阿尔茨海默病的新风险位点 HAVCR2 在调节神经退行性小胶质细胞反应中的作用
  • 批准号:
    10608400
  • 财政年份:
    2023
  • 资助金额:
    $ 82.86万
  • 项目类别:
Gender-dependent APOE4 regulation of neutrophil-microglia crosstalk in Alzheimer's disease
阿尔茨海默病中中性粒细胞-小胶质细胞串扰的性别依赖性 APOE4 调节
  • 批准号:
    10344242
  • 财政年份:
    2022
  • 资助金额:
    $ 82.86万
  • 项目类别:
Gender-dependent APOE4 regulation of neutrophil-microglia crosstalk in Alzheimer's disease
阿尔茨海默病中中性粒细胞-小胶质细胞串扰的性别依赖性 APOE4 调节
  • 批准号:
    10552667
  • 财政年份:
    2022
  • 资助金额:
    $ 82.86万
  • 项目类别:
APOE e4 negative regulation of microglia-astrocytes crosstalk in Alzheimer's disease
APOE e4 对阿尔茨海默病中小胶质细胞-星形胶质细胞串扰的负调节
  • 批准号:
    10429190
  • 财政年份:
    2022
  • 资助金额:
    $ 82.86万
  • 项目类别:
Xenon gas treatment to modulate microglia in neurodegenerative diseases
氙气治疗调节神经退行性疾病中的小胶质细胞
  • 批准号:
    10617078
  • 财政年份:
    2021
  • 资助金额:
    $ 82.86万
  • 项目类别:
Xenon gas treatment to modulate microglia in neurodegenerative diseases
氙气治疗调节神经退行性疾病中的小胶质细胞
  • 批准号:
    10259094
  • 财政年份:
    2021
  • 资助金额:
    $ 82.86万
  • 项目类别:
Targeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimer's disease
靶向 miR-155 和 APOE-TREM2 通路以恢复阿尔茨海默病中功能失调的小胶质细胞
  • 批准号:
    9926784
  • 财政年份:
    2017
  • 资助金额:
    $ 82.86万
  • 项目类别:
Role of Microglia in Retinitis Pigementosa
小胶质细胞在色素性视网膜炎中的作用
  • 批准号:
    9899490
  • 财政年份:
    2017
  • 资助金额:
    $ 82.86万
  • 项目类别:
Microglial mechanisms of postoperative CNS inflammation and cognitive decline
术后中枢神经系统炎症和认知能力下降的小胶质细胞机制
  • 批准号:
    9010611
  • 财政年份:
    2016
  • 资助金额:
    $ 82.86万
  • 项目类别:
Restoration of homeostatic microglia in CNS inflammation
中枢神经系统炎症中小胶质细胞稳态的恢复
  • 批准号:
    10426253
  • 财政年份:
    2014
  • 资助金额:
    $ 82.86万
  • 项目类别:

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