Homeostasis in Adult Vessels

成人血管的稳态

• 批准号: 9386060
• 负责人: M. LUISA IRUELA-ARISPE
• 金额: $ 12.23万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386060
• 关键词: 3' Untranslated Regions; Acceleration; Adult; 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; 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; recruit; response; senescence; transcription factor; transcriptome sequencing; western diet

 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)：这项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提供固有保护的因素。在这项提案中，我们将重点关注NOTCH1，一种细胞表面受体和转录因子，基于初步数据，它为静止的(内稳态)内皮细胞提供抗炎表型。NOTCH1在体内由成年小鼠和人血管内皮细胞结构性表达。人内皮细胞中NOTCH1转录本的减少或小鼠中Notch1的遗传失活在没有任何额外伤害的情况下触发了炎症反应。内皮细胞暴露在西方饮食、氧化磷脂(Ox-PAPC)以及炎性细胞因子中，导致内源性NOTCH1(及其靶基因)迅速减少。通过对147名人类供者的内皮细胞进行基因芯片分析，我们观察到基础水平和Ox-PAPC处理后的NOTCH1水平的差异，并确定了一个与Ox-PAPC对内皮细胞对NOTCH1的反应有关的基因座。在包括100,000人在内的大规模GWA中，这个相同的基因座也与高密度脂蛋白水平有关。该项目的研究将检验这样一种假设，即循环中的脂质减少NOTCH1有助于 动脉粥样硬化病变的典型的长时间炎症。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，成年小鼠内皮细胞中Notch1的遗传失活会导致白细胞的渗透、脱落和内皮细胞的丢失 从内膜上看。此外，利用芯片方法，我们发现NOTCH1调节Tristetraprolin，一种针对3‘UTR中的ARES序列的RNA结合蛋白，导致编码一组炎症细胞因子的mRNAs的不稳定，这与内皮稳态和抑制炎症相一致。这一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是必不可少的。为了验证这一假设，我们提出了两个特定的目标：1.确定NOTCH1在成人动脉内皮细胞中表达和功能的调控机制(S)；2.确定NOTCH1在静止的动脉内皮细胞中维持抗炎状态的分子途径。