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.

描述（由申请人提供）：该研究的长期目标是确定在动脉粥样硬化和炎症的初始阶段可以为内皮细胞提供固有保护的因素。在本提案中，我们将重点关注 NOTCH1，一种细胞。根据初步数据，NOTCH1 为静止（稳态）内皮细胞提供抗炎表型，由小鼠和人类的成年内皮细胞组成型表达。在没有任何额外损伤的情况下，人内皮细胞中 NOTCH1 转录物的减少或小鼠中 Notch1 的基因失活也会引发炎症反应。使用来自 147 个人的内皮细胞的微阵列分析，导致内源性 NOTCH1（及其靶基因）迅速减少。供体中，我们观察了基础和 Ox-PAPC 处理的 NOTCH1 水平的差异，并确定了一个与 Ox-PAPC 内皮细胞对 NOTCH1 的反应相关的位点，该位点也与大规模 GWAS 中的 HDL 水平相关。该项目将对 100,000 人进行研究，验证循环脂质有助于减少 NOTCH1 的假设。事实上，动脉粥样硬化易感背景（Apoe 或 Ldlr 缺失小鼠）中 NOTCH1 水平的降低会促进动脉粥样硬化的加速并导致更大的病变。此外，Notch1 在成人内皮细胞中的基因失活。小鼠导致白细胞浸润、脱落和内皮细胞丢失此外，与内皮稳态和抑制炎症中的作用一致，使用 ChIP 方法，我们发现 NOTCH1 调节 tristetraprolin，这是一种 RNA 结合蛋白，靶向编码一组 mRNA 的 3'UTR 不稳定中的 ARE 序列。该应用的中心假设是内皮细胞中的 NOTCH1 对于维持血液和组织之间的抗炎界面至关重要。我们提出了两个具体目标：1.确定成人动脉内皮细胞中NOTCH1表达和功能的控制机制；2.确定NOTCH1在静止动脉内皮细胞中维持抗炎状态的分子途径。