Homeostasis in Adult Vessels

成人血管的稳态

基本信息

批准号：
9198964
负责人：
M. LUISA IRUELA-ARISPE
金额：
$ 38.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198964
关键词：
3&apos Untranslated Regions Acceleration Adult Alpha Cell Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Arteries Atherosclerosis Basement membrane Blood Blood Vessels CXCL12 gene Cardiovascular Diseases Cell Surface Receptors Cells ChIP-seq Clinical Trials Collaborations Conflict (Psychology)Data Development Diet Dietary Fats Dissociation Down-Regulation Endothelial Cells Endothelium Event Exhibits Exposure to Gene Targeting Genes Genetic Genomics Goals Harvest High Density Lipoproteins Homeostasis Human In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Investigation Knockout Mice Lead Lesion Letters Leukocytes Link Lipids Maintenance Manuscripts Mediator of activation protein Messenger RNA Microarray Analysis Molecular Mus NOTCH1 gene Oxides Pathway interactions Phenotype Phospholipids Predisposing Factor Prevention Process Proteins RNA-Binding Proteins Recruitment Activity Regulation Reporting Role Series Signal Pathway Signal Transduction Small Interfering RNA Surface TIS11 protein Testing Tissues Transcript athero susceptible atheroprotective base cancer therapy cohort cytokine design experimental study genome wide association study in vivo interest mouse model notch protein overexpression oxidized phosphatidyl choline pressure prevent programs public health relevance receptor response senescence transcription factor transcriptome sequencing western diet

3&apos Untranslated Regions Acceleration Adult Alpha Cell Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Arteries Atherosclerosis Basement membrane Blood Blood Vessels CXCL12 gene Cardiovascular Diseases Cell Surface Receptors Cells ChIP-seq Clinical Trials Collaborations Conflict (Psychology)Data Development Diet Dietary Fats Dissociation Down-Regulation Endothelial Cells Endothelium Event Exhibits Exposure to Gene Targeting Genes Genetic Genomics Goals Harvest High Density Lipoproteins Homeostasis Human In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Investigation Knockout Mice Lead Lesion Letters Leukocytes Link Lipids Maintenance Manuscripts Mediator of activation protein Messenger RNA Microarray Analysis Molecular Mus NOTCH1 gene Oxides Pathway interactions Phenotype Phospholipids Predisposing Factor Prevention Process Proteins RNA-Binding Proteins Recruitment Activity Regulation Reporting Role Series Signal Pathway Signal Transduction Small Interfering RNA Surface TIS11 protein Testing Tissues Transcript athero susceptible atheroprotective base cancer therapy cohort cytokine design experimental study genome wide association study in vivo interest mouse model notch protein overexpression oxidized phosphatidyl choline pressure prevent programs public health relevance receptor response senescence transcription factor transcriptome sequencing western diet

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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.

描述（由适用提供）：这一调查线的长期目标是确定可以在动脉粥样硬化和炎症的初始阶段为实地提供固有保护的因素。在此提案中，我们将重点介绍Notch1，即细胞表面受体和转录因子，基于初步数据，它为静态（稳态）冬季提供了抗炎表型。 Notch1由小鼠和人体内的成年植物植物组成性表达。在没有任何其他侮辱的情况下，小鼠的体外或遗传失活的Notch1转录本在体外或遗传失活中会触发炎症反应。接触森林细胞对西方饮食，氧化磷脂（OX-PAPC）以及炎性细胞因子的暴露导致内源性Notch1（以及其靶基因）迅速降低。使用来自147名人类供体的内皮细胞的微阵列分析，我们观察到基本和OXPAPC处理的Notch1水平的差异，并确定了与OXPAPC对内皮细胞对Notch1响应的响应相关的基因座。同样的基因座也与包括100,000人在内的大规模GWA中的HDL水平有关。该项目的研究将检验以下假设：循环脂质减少Notch1的假设有助于到典型的动脉粥样硬化病变的长时间炎症。实际上，在可动脉粥样硬化的背景（APOE或LDLR无效小鼠）中降低Notch1水平会促进动脉粥样硬化的加速，并导致较大的病变。此外，成年小鼠内皮中Notch1的遗传失活导致白细胞浸润，脱落和内皮细胞的丧失来自内饰。此外，使用芯片方法，我们发现Notch1调节Tristetraprolin是一种靶向3'UTR中Ares序列的RNA结合蛋白，并与3'UTR的RNA结合蛋白进行调节，并与炎症方法的作用一致，并且抑制了炎症性的抑制作用。该应用的中心假设是，内皮中的Notch1对于维持血液和组织之间的抗炎界面至关重要。为了检验这一假设，我们提出了两个具体目的：1。确定控制成年动脉内皮中Notch1表达和功能的机制； 2。确定Notch1在静态动脉内皮中保持抗炎状态的分子途径。