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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

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.