Neuroinflammation and vascular development in GMH

GMH 的神经炎症和血管发育

基本信息

  • 批准号:
    10685146
  • 负责人:
  • 金额:
    $ 58.07万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-01 至 2028-07-31
  • 项目状态:
    未结题

项目摘要

SUMMARY Preterm infants born between 21 to 30 gestational weeks (GW) have 20-40% chance of developing germinal matrix hemorrhage (GMH), which is a leading cause of neonatal mortality and neurodevelopmental disorders, such as cerebral palsy. Despite decades of research, however, there has been no significant improvement in the prevalence of preterm birth and the mechanism leading to GMH remains unclear. To understand the cause(s) for GMH, we have shown that, during the second trimester, germinal matrix contains enriched populations of Nestin+ radial glia and DCX+ neuroblasts that are fated to become GABAergic interneurons. Furthermore, DCX+ neuroblasts in the germinal matrix are organized as distinct clusters, called DCX-Enriched Nests or DENs, where they expand and migrate to the cerebral cortex and other deep nuclei before becoming mature GABAergic interneurons and integrating into the local neural circuits. To investigate why blood vessels in the germinal matrix are particularly vulnerable to develop GMH, we combined histological and ultrastructural analyses, fluorescence- activated cell sorting (FACS), and single-cell transcriptomics to characterize the properties of nascent blood vessels in the prenatal human brain from 15 to 25 GW. These studies lead to three main conclusions. First, during the second trimester the vascular network in the germinal matrix is much more complex than other brain regions. These nascent blood vessels are tiled by an ensemble of endothelial cells and mural cells, which follow distinct developmental trajectories and use diverse signaling mechanisms to facilitate cell-cell communication and maturation. Second, endothelial cells from younger brain (15-18 GW) exhibit stage-specific transcriptomic and bioenergetic features that are different from those from 20-23 GW. In addition, microglia-vasculature interactions stage-dependently promote angiogenesis in the germinal matrix, but not in the cortical plate. Finally, transcriptomic profiling of CD45+ cells in GMH cases showed that proinflammatory neutrophils and monocytes utilize antibacterial factors and CXCL16-S1PR1 signaling, respectively, to disrupt nascent vasculature in the germinal matrix. Collectively, our results support the overarching hypothesis that proinflammatory neutrophils and monocytes produce cytotoxic factors to disrupt angiogenesis and neurogenesis in the germinal matrix of preterm infants with GMH. To test this hypothesis, we propose to (1) characterize the cytotoxic properties of neutrophil-produced antibacterial factors in disrupting angiogenesis, (2) determine the impacts of CXCL16-S1PR1-mediated signaling in angiogenesis in the germinal matrix, and (3) examine the impacts of GMH on the neurogenesis and migration of GABAergic interneurons. Results from this project will provide important insights into disease mechanism of, and therapeutic targets for, GMH.
总结

项目成果

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Eric J Huang其他文献

Eric J Huang的其他文献

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{{ truncateString('Eric J Huang', 18)}}的其他基金

Endolysosomal trafficking and lipid metabolism defects in FTLD
FTLD 中的内溶酶体运输和脂质代谢缺陷
  • 批准号:
    10645964
  • 财政年份:
    2023
  • 资助金额:
    $ 58.07万
  • 项目类别:
Single Cell Characterization of FTLD-GRN
FTLD-GRN 的单细胞表征
  • 批准号:
    10514141
  • 财政年份:
    2022
  • 资助金额:
    $ 58.07万
  • 项目类别:
Progranulin deficiency and microglia senescence in neurodegeneration
神经退行性变中颗粒体蛋白前体缺乏和小胶质细胞衰老
  • 批准号:
    10044228
  • 财政年份:
    2020
  • 资助金额:
    $ 58.07万
  • 项目类别:
Progranulin deficiency and microglia senescence in neurodegeneration
神经退行性变中颗粒体蛋白前体缺乏和小胶质细胞衰老
  • 批准号:
    10222564
  • 财政年份:
    2020
  • 资助金额:
    $ 58.07万
  • 项目类别:
Progranulin deficiency and microglia senescence in neurodegeneration
神经退行性变中颗粒体蛋白前体缺乏和小胶质细胞衰老
  • 批准号:
    10456803
  • 财政年份:
    2020
  • 资助金额:
    $ 58.07万
  • 项目类别:
Progranulin deficiency and microglia senescence in neurodegeneration
神经退行性变中颗粒体蛋白前体缺乏和小胶质细胞衰老
  • 批准号:
    10681318
  • 财政年份:
    2020
  • 资助金额:
    $ 58.07万
  • 项目类别:
Single Cell Analyses of Neuroimmune Dysfunctions in the Thalamocortical Circuit in FTLD
FTLD 丘脑皮质回路神经免疫功能障碍的单细胞分析
  • 批准号:
    10442528
  • 财政年份:
    2018
  • 资助金额:
    $ 58.07万
  • 项目类别:
Single Cell Analyses of Neuroimmune Dysfunctions in the Thalamocortical Circuit in FTLD
FTLD 丘脑皮质回路神经免疫功能障碍的单细胞分析
  • 批准号:
    10207374
  • 财政年份:
    2018
  • 资助金额:
    $ 58.07万
  • 项目类别:
Diversity Supplement: Single Cell Analyses of Neuroimmune Dysfunctions in the Thalamocortical Circuit in FTLD
多样性补充:FTLD 丘脑皮质回路神经免疫功能障碍的单细胞分析
  • 批准号:
    10403045
  • 财政年份:
    2018
  • 资助金额:
    $ 58.07万
  • 项目类别:
A Cellular Resolution Census of the Developing Human Brain
人类大脑发育的细胞分辨率普查
  • 批准号:
    10165826
  • 财政年份:
    2017
  • 资助金额:
    $ 58.07万
  • 项目类别:

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抗菌药物靶向递送新技术
  • 批准号:
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  • 财政年份:
    2015
  • 资助金额:
    $ 58.07万
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  • 批准号:
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    2012
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Targeting bacterial phosphatases for novel anti-bacterial agents.
针对细菌磷酸酶的新型抗菌剂。
  • 批准号:
    8298885
  • 财政年份:
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