Homeostasis in Adult Vessels

成人血管的稳态

基本信息

项目摘要

 DESCRIPTION (provided by applicant): The long term goal of this line of investigation is to identify the factors that can provide inherent protection to the endothelium during the initial stages of atherosclerosis and inflammation. In this proposal, we will focus on NOTCH1, a cell surface receptor and transcription factor that, based on preliminary data, provides an anti-inflammatory phenotype to quiescent (homeostatic) endothelium. NOTCH1 is constitutively expressed by the adult endothelium of mouse and human vessels in vivo. Reduction of NOTCH1 transcripts in human endothelium in vitro or genetic inactivation of Notch1 in mice triggers an inflammatory response in the absence of any additional insult. Exposure of endothelial cells to Western diet, oxidized phospholipids (Ox- PAPC), as well as inflammatory cytokines, results in a rapid reduction in endogenous NOTCH1 (together with its target genes). Using microarray analyses of endothelial cells from 147 human donors, we observed differences in basal and Ox-PAPC treated levels of NOTCH1 and identified a locus that was associated with the response of endothelial cells to NOTCH1 by Ox-PAPC. This same locus was also associated with HDL levels in a large scale GWAS including 100,000 humans. Studies in this project will test the hypothesis that reduction of NOTCH1 by circulating lipids contributes to the prolonged inflammation typical of atherosclerosis lesions. In fact, reduction of NOTCH1 levels in an athero-susceptible background (Apoe or Ldlr null mice) promotes acceleration of atherosclerosis and results in larger lesions. Furthermore, genetic inactivation of Notch1 in the endothelium of adult mice leads to leukocyte infiltration, detachment and loss of endothelial cells from the intima. In addition and consistent with a role in endothelial homeostasis and suppression of inflammation, using a ChIP approach we found that NOTCH1 regulates tristetraprolin, an RNA binding protein that targets to AREs sequences in the 3'UTR causing destabilization of mRNAs encoding a cohort of inflammatory cytokines. The central hypothesis of this application is that NOTCH1 in the endothelium is essential to maintain an anti-inflammatory interface between blood and tissue. To test this hypothesis, we propose two specific aims: 1. To determine the mechanism(s) that control NOTCH1 expression and function in adult arterial endothelium; and 2. To identify the molecular pathways by which NOTCH1 maintains an anti-inflammatory status in the endothelium of quiescent arteries.


项目成果

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M. LUISA IRUELA-ARISPE其他文献

M. LUISA IRUELA-ARISPE的其他文献

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{{ truncateString('M. LUISA IRUELA-ARISPE', 18)}}的其他基金

REWIRING CANCER-INDUCED ABNORMALITIES IN THE VASCULAR BARRIER
重塑血管屏障中癌症引起的异常
  • 批准号:
    10915752
  • 财政年份:
    2023
  • 资助金额:
    $ 38.5万
  • 项目类别:
Underlying Mechanisms in Angiosarcoma
血管肉瘤的潜在机制
  • 批准号:
    10058167
  • 财政年份:
    2020
  • 资助金额:
    $ 38.5万
  • 项目类别:
Vascular Growth and Regeneration
血管生长和再生
  • 批准号:
    10542405
  • 财政年份:
    2018
  • 资助金额:
    $ 38.5万
  • 项目类别:
Vascular Growth and Regeneration
血管生长和再生
  • 批准号:
    10359709
  • 财政年份:
    2018
  • 资助金额:
    $ 38.5万
  • 项目类别:
Homeostasis in Adult Vessels
成人血管的稳态
  • 批准号:
    9386060
  • 财政年份:
    2015
  • 资助金额:
    $ 38.5万
  • 项目类别:
Underlying Mechanisms in Angiosarcoma
血管肉瘤的潜在机制
  • 批准号:
    9301291
  • 财政年份:
    2015
  • 资助金额:
    $ 38.5万
  • 项目类别:
Underlying Mechanisms in Angiosarcoma
血管肉瘤的潜在机制
  • 批准号:
    9087211
  • 财政年份:
    2015
  • 资助金额:
    $ 38.5万
  • 项目类别:
Targeting VEGF-mediated Tumor Angiogenesis in Cancer Therapy
癌症治疗中靶向 VEGF 介导的肿瘤血管生成
  • 批准号:
    8719790
  • 财政年份:
    2014
  • 资助金额:
    $ 38.5万
  • 项目类别:
16th Annual International Vascular Biology Meeting
第 16 届国际血管生物学年会
  • 批准号:
    7915981
  • 财政年份:
    2010
  • 资助金额:
    $ 38.5万
  • 项目类别:
Cancer Cell Biology
癌细胞生物学
  • 批准号:
    7944540
  • 财政年份:
    2009
  • 资助金额:
    $ 38.5万
  • 项目类别:

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