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
- 来源:
- 关键词:AgonistAnti-Bacterial AgentsBioenergeticsBioinformaticsBiological AssayBlood VesselsBrainBrain regionCell CommunicationCell MaturationCell NucleusCellsCellular StressCerebral PalsyCerebral cortexComplexDataDefensinsDevelopmentDiseaseDisease modelElastasesEndothelial CellsEnzymesErythroExhibitsFluorescence-Activated Cell SortingHistologicHumanIn VitroInflammatoryInterneuronsKnowledgeLeadMacrophageMediatingMicrogliaMolecularMorphogenesisMyelogenousNeonatal MortalityNeurodevelopmental DisorderNeurogliaNeuroimmuneOrganoidsPTPRC genePathogenesisPerinatal subependymal hemorrhagePeroxidasesPopulationPregnancyPremature BirthPremature InfantPrevalencePropertyRadialResearchResearch Project GrantsRoleSecond Pregnancy TrimesterSignal TransductionTestingangiogenesisantagonistcytotoxicimprovedinsightmatrigelmigrationmonocyteneonatal deathnerve stem cellnestin proteinneural circuitneuroblastneurogenesisneuroinflammationneuropathologyneutrophilprenatalprogenitorsingle-cell RNA sequencingstem cell biologytherapeutic targettranscriptomic profilingtranscriptomics
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
在21至30孕周(GW)之间出生的早产儿有20-40%的机会发展为老年痴呆症
基质出血(GMH),是新生儿死亡和神经发育障碍的主要原因,
例如脑瘫。然而,尽管经过几十年的研究,
早产的发生率和导致GMH的机制仍不清楚。了解原因
对于GMH,我们已经表明,在孕中期,germinal矩阵包含丰富的
巢蛋白+放射状胶质细胞和DCX+神经母细胞,它们注定成为GABA能中间神经元。此外,DCX+
在生发基质中的神经母细胞被组织成不同的簇,称为富含DCX的巢或DEN,其中
它们在变成成熟的GABA能前扩展并迁移到大脑皮层和其他深层核团
中间神经元并整合到局部神经回路中。为了研究为什么血管在生殖基质中
特别容易发展成GMH,我们结合了组织学和超微结构分析,荧光-
活化细胞分选(FACS)和单细胞转录组学来表征新生血液的性质
胎儿大脑中的血管从15到25 GW。这些研究得出三个主要结论。第一、
在孕中期,胚基质中的血管网络比其他脑组织复杂得多,
地区这些新生血管由内皮细胞和壁细胞的集合体平铺,
不同的发育轨迹,并使用不同的信号机制,以促进细胞间的沟通
和成熟。第二,来自年轻脑(15-18 GW)的内皮细胞表现出阶段特异性转录组学特征。
和不同于20-23 GW的生物能量特征。此外,小胶质血管
相互作用阶段依赖性地促进生发基质中的血管生成,但不促进皮质板中的血管生成。最后,
GMH病例中CD 45+细胞的转录组学分析显示,促炎性中性粒细胞和单核细胞
分别利用抗菌因子和CXCL 16-S1 PR 1信号传导来破坏新生血管系统。
几何矩阵总的来说,我们的研究结果支持总体假设,即促炎性
嗜中性粒细胞和单核细胞产生细胞毒性因子,破坏血管生成和神经发生,
患有GMH的早产儿的生发基质。为了验证这一假设,我们建议(1)描述
嗜热菌产生的抗菌因子在破坏血管生成中的细胞毒性特性,(2)确定
CXCL 16-S1 PR 1介导的信号传导对生殖基质中血管生成的影响,以及(3)检查CXCL 16-S1 PR 1介导的信号传导对生殖基质中血管生成的影响。
GMH对GABA能中间神经元的神经发生和迁移的影响。该项目的成果将
为GMH的发病机制和治疗靶点提供了重要的见解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Eric J Huang其他文献
Eric J Huang的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
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:
相似海外基金
New technologies for targeted delivery of anti-bacterial agents
抗菌药物靶向递送新技术
- 批准号:
1654774 - 财政年份:2015
- 资助金额:
$ 58.07万 - 项目类别:
Studentship
Targeting bacterial phosphatases for novel anti-bacterial agents.
针对细菌磷酸酶的新型抗菌剂。
- 批准号:
8416313 - 财政年份:2012
- 资助金额:
$ 58.07万 - 项目类别:
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:2012
- 资助金额:
$ 58.07万 - 项目类别: