Pericyte angiopoietin2 and neonatal intracranial hemorrhage
周细胞血管生成素2与新生儿颅内出血
基本信息
- 批准号:10288547
- 负责人:
- 金额:$ 46.06万
- 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:2021-07-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsANGPT2 geneAgeAgonistAngiopoietin-2AngiopoietinsApoptosisBasement membraneBindingBiological AssayBlood - brain barrier anatomyBlood VesselsBlood capillariesBrainBrain hemorrhageCASP5 geneCell ProliferationCellsCellular MorphologyCerebral PalsyCerebral hemisphere hemorrhageCognitive deficitsCollectionComplicationConditioned Culture MediaEmbryoEndothelial CellsEpendymaEpigenetic ProcessFollow-Up StudiesFoundationsFutureGene DeletionGoalsGrantHDAC2 geneHemorrhageHistone AcetylationHistone DeacetylaseHumanImmunohistochemistryIntracranial HemorrhagesLeadLigandsMADH2 geneMediatingMessenger RNAMicroRNAsMorbidity - disease rateMusNeonatalNeuraxisNeuronsPathogenesisPericytesPerinatal subependymal hemorrhagePermeabilityPhenotypePlayPopulationPregnancyPremature InfantProteinsProteomicsPublishingRNA Polymerase IIRegulationReportingRoleSamplingSignal TransductionSmall Interfering RNATEK geneTGF-beta type I receptorTIMP3 geneTestingTight JunctionsTissuesTranscriptTransforming Growth Factor betaTransforming Growth FactorsTransgenic MiceTubeVentricularblood-brain barrier disruptionblood-brain barrier permeabilizationbrain endothelial cellchromatin immunoprecipitationexperimental studyfollow-upgene repressionhistone deacetylase 2human RNA sequencinginsightintraventricular hemorrhageknock-downmigrationmortalitymutantnovel strategiesnovel therapeutic interventionnovel therapeuticspreventpromoterreceptorstemtranscriptomicswhite matter
项目摘要
Project Summary / Abstract
Intraventricular hemorrhage (IVH) is a debilitating condition at any age but is especially common and
devastating in premature infants as it is associated with substantial long-term morbidity (e.g., cerebral palsy,
cognitive deficits) and mortality in this population. In premature infants, most IVH stems from hemorrhage in
the germinal matrix (GM), a collection of highly vascularized neuronal and glial precursor located underneath
the ventricular ependyma. Pericytes (PCs) and endothelial cells (ECs) are key components of the blood-brain
barrier (BBB). In the GM, reduction in the numbers of PCs and levels of the ligand transforming growth factor
(TGF)-β1 in comparison to the white matter and cortex has been implicated in the high propensity of the GM to
hemorrhage. Indeed, we previously reported that deletion of the gene encoding activin receptor-like kinase 5
(ALK5), a type I TGFβ receptor, in PCs leads to gross GM hemorrhage (GMH)-IVH in embryonic mice (Dev
Cell, 44:665) largely through effects on ECs. However, mechanisms underlying these non-cell autonomous
effects on ECs are incompletely defined. To search for PC-derived factors that may signal to ECs, we
conducted bulk RNA-sequencing of human brain PCs with and without both siRNA Alk5 knockdown and
TGFβ1 treatment and identified the secreted factor angiopoietin (Angpt) 2. ANGPT2, which is broadly
implicated in EC tube destabilization and/or remodeling, is predominantly expressed by ECs, but PC
expression has not been reported. Moreover, the role ANGPT2, and certainly PC-derived ANGPT2, in GMH-
IVH has not been studied. Follow-up studies confirmed that TGFβ1 treatment of human brain PCs rapidly and
robustly down-regulates levels of Angpt2 mRNA (~65% and ~90% reduction in 3 h and 12 h, respectively) and
protein in an ALK5-dependent manner. This rapid reduction in Angpt2 mRNA suggests agonist-induced
transcript destabilization, which we will investigate in the proposed experiments. Furthermore, chromatin
immunoprecipitation assays revealed that TGFβ1 treatment of PCs promotes epigenetic and transcriptional
repression of Angpt2, increasing histone deacetylase-2 binding and reducing histone acetylation (H3K9ac,
H3K27ac) and RNA polymerase II binding to the proximal promoter. Finally, in mice with Alk5 deletion in PCs,
perivascular ANGPT2 expression is markedly increased. Thus, we hypothesize that when TGFβ-ALK5
signaling in PCs is disrupted, ANGPT2 levels are increased, destabilizing ECs and leading to disruption of the
BBB and GMH-IVH. We will use cultured human brain vascular cells, transgenic mice, proteomic and
3’UTR/microRNA screens and de-identified human brain samples to test this hypothesis in two specific aims:
1) determine mechanisms of TGFβ-mediated regulation of Angpt2 in PCs and effects on ECs; and 2) elucidate
role of PC ANGPT2 in GMH-IVH of mice and humans. This R21 will yield key insights into BBB formation and
GMH-IVH pathogenesis and form the foundation of a subsequent high impact R01 grant that will provide
concrete steps towards devising novel therapeutic strategies for brain hemorrhage.
项目摘要/摘要
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)
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Daniel Greif其他文献
Daniel Greif的其他文献
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{{ truncateString('Daniel Greif', 18)}}的其他基金
Epigenetic-mediated Notch pathway activation promotes elastin aortopathy
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Novel vascular smooth muscle cell progenitors in development and disease
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Novel vascular smooth muscle cell progenitors in development and disease
发育和疾病中的新型血管平滑肌细胞祖细胞
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10433824 - 财政年份:2020
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Pathological arterial muscularization and the role of integrins
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Mural cell TGF-beta-mediated signaling and neonatal intracerebral hemorrhage
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Pathological arterial muscularization and the role of integrins
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8212890 - 财政年份:2008
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