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

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)

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 }}

Daniel Greif其他文献

Daniel Greif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('Daniel Greif', 18)}}的其他基金

Epigenetic-mediated Notch pathway activation promotes elastin aortopathy
表观遗传介导的Notch通路激活促进弹性蛋白主动脉病
  • 批准号:
    10595308
  • 财政年份:
    2023
  • 资助金额:
    $ 46.06万
  • 项目类别:
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
  • 批准号:
    10670304
  • 财政年份:
    2020
  • 资助金额:
    $ 46.06万
  • 项目类别:
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
  • 批准号:
    9893632
  • 财政年份:
    2020
  • 资助金额:
    $ 46.06万
  • 项目类别:
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
  • 批准号:
    10433824
  • 财政年份:
    2020
  • 资助金额:
    $ 46.06万
  • 项目类别:
Vascular disease pathogenesis: the interface of smooth muscle and immune cells
血管疾病发病机制:平滑肌与免疫细胞的界面
  • 批准号:
    9769127
  • 财政年份:
    2018
  • 资助金额:
    $ 46.06万
  • 项目类别:
Pathological arterial muscularization and the role of integrins
病理性动脉肌化和整合素的作用
  • 批准号:
    8800479
  • 财政年份:
    2014
  • 资助金额:
    $ 46.06万
  • 项目类别:
Mural cell TGF-beta-mediated signaling and neonatal intracerebral hemorrhage
壁细胞TGF-β介导的信号传导与新生儿脑出血
  • 批准号:
    8772010
  • 财政年份:
    2014
  • 资助金额:
    $ 46.06万
  • 项目类别:
Pathological arterial muscularization and the role of integrins
病理性动脉肌化和整合素的作用
  • 批准号:
    8969702
  • 财政年份:
    2014
  • 资助金额:
    $ 46.06万
  • 项目类别:
Morphogenesis of the pulmonary artery smooth muscle layer
肺动脉平滑肌层的形态发生
  • 批准号:
    8308488
  • 财政年份:
    2008
  • 资助金额:
    $ 46.06万
  • 项目类别:
Morphogenesis of the pulmonary artery smooth muscle layer
肺动脉平滑肌层的形态发生
  • 批准号:
    8212890
  • 财政年份:
    2008
  • 资助金额:
    $ 46.06万
  • 项目类别:

相似海外基金

Impact of alternative polyadenylation of 3'-untranslated regions in the PI3K/AKT cascade on microRNA
PI3K/AKT 级联中 3-非翻译区的替代多聚腺苷酸化对 microRNA 的影响
  • 批准号:
    573541-2022
  • 财政年份:
    2022
  • 资助金额:
    $ 46.06万
  • 项目类别:
    University Undergraduate Student Research Awards
How do untranslated regions of cannabinoid receptor type 1 mRNA determine receptor subcellular localisation and function?
1 型大麻素受体 mRNA 的非翻译区如何决定受体亚细胞定位和功能?
  • 批准号:
    2744317
  • 财政年份:
    2022
  • 资助金额:
    $ 46.06万
  • 项目类别:
    Studentship
MICA:Synthetic untranslated regions for direct delivery of therapeutic mRNAs
MICA:用于直接递送治疗性 mRNA 的合成非翻译区
  • 批准号:
    MR/V010948/1
  • 财政年份:
    2021
  • 资助金额:
    $ 46.06万
  • 项目类别:
    Research Grant
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
  • 批准号:
    10019570
  • 财政年份:
    2019
  • 资助金额:
    $ 46.06万
  • 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
  • 批准号:
    10223370
  • 财政年份:
    2019
  • 资助金额:
    $ 46.06万
  • 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
  • 批准号:
    10455108
  • 财政年份:
    2019
  • 资助金额:
    $ 46.06万
  • 项目类别:
Synergistic microRNA-binding sites, and 3' untranslated regions: a dialogue of silence
协同的 microRNA 结合位点和 3 非翻译区:沉默的对话
  • 批准号:
    255762
  • 财政年份:
    2012
  • 资助金额:
    $ 46.06万
  • 项目类别:
    Operating Grants
Analysis of long untranslated regions in Nipah virus genome
尼帕病毒基因组长非翻译区分析
  • 批准号:
    20790351
  • 财政年份:
    2008
  • 资助金额:
    $ 46.06万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Search for mRNA elements involved in the compatibility between 5' untranslated regions and coding regions in chloroplast translation
寻找参与叶绿体翻译中 5 非翻译区和编码区之间兼容性的 mRNA 元件
  • 批准号:
    19370021
  • 财政年份:
    2007
  • 资助金额:
    $ 46.06万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Post-transcriptional Regulation of PPAR-g Expression by 5'-Untranslated Regions
5-非翻译区对 PPAR-g 表达的转录后调控
  • 批准号:
    7131841
  • 财政年份:
    2006
  • 资助金额:
    $ 46.06万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了