microRNA regulation of endothelial functions

microRNA对内皮功能的调节

• 批准号: 8444656
• 负责人: William C Sessa
• 金额: $ 44.77万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-06 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444656
• 关键词: 3' Untranslated Regions; Area; Base Pairing; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cell Cycle; Cellular biology; Data; Dicer Enzyme; Employee Strikes; Endothelial Cells; Endothelium; Enzymes; Exhibits; Fibroblast Growth Factor 2; Functional disorder; Gene Expression; Genome; Grant; Growth Factor; Heart Diseases; Human; In Vitro; Ischemia; Messenger RNA; MicroRNAs; Modeling; Morphogenesis; Mus; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Process; Proteins; Public Health; Quality of life; Regulation; Regulator Genes; Research; Research Support; Role; Signal Transduction; Testing; Time; Tissues; Transduction Gene; Transgenic Mice; Translations; Untranslated RNA; Vascular Endothelial Growth Factors; Work; angiogenesis; atherogenesis; cell growth; cell type; human DICER1 protein; human NOS3 protein; implantation; improved; in vivo; insight; mimicry; novel therapeutic intervention; public health relevance; research study; response; stem; therapeutic target; tumor

DESCRIPTION (provided by applicant): The specific roles of miRNAs in vascular function are just beginning to be explored. Our previous work has shown that reduction of overall miRNA levels via Dicer silencing in human endothelial cells (EC) strongly regulates angiogenic gene expression and impairs aspects of in vitro angiogenesis including EC growth and morphogenesis. These in vitro experiments are supported by new exciting preliminary data in vivo data using mice conditionally lacking the rate limiting enzyme (Dicer) in miRNA synthesis in EC. Mice lacking Dicer in EC (EC specific Dicer KO) are viable but exhibit impaired post-natal angiogenic responses. In order to dissect the relationships between signal transduction, gene expression and miRNAs in EC, we show that treatment of EC with VEGF stimulates time-dependent changes in global miRNA profiles and show that components of the miRNA cluster, miR 17-92 can regulate aspects of VEGF induced cell growth and morphogenesis. In addition, we have identified a specific miRNA (miR-155) that regulates the levels of endothelial nitric oxide synthase (eNOS) in cultured EC. Thus, we hypothesize that Dicer generated endothelial miRNAs regulate the extent of angiogenesis and blood flow control in vivo by regulating mRNA levels and/or the translational stability of important proteins. We will: 1. Identify and characterize angiogenic growth factor regulated miRNAs in EC; 2. Define the roles of miR 17-92 in models of angiogenesis and 3. Define the roles of miR-155 in regulating eNOS function in vitro and in vivo. Collectively, this work will facilitate the understanding of the importance of miRNAs in EC biology and shed insights into their role as potential therapeutics targets.

描述（由申请人提供）：刚刚开始探索miRNA在血管功能中的特定作用。我们先前的工作表明，通过人体内皮细胞（EC）中的丁香液沉默降低了总体miRNA水平（EC）强烈调节血管生成基因的表达，并损害体外血管生成的各个方面，包括EC生长和形态发生。这些体外实验由在EC中有条件地缺乏限制速率限制酶（DICER）的小鼠在体内数据中得到了新的刺激初步数据的支持。在EC（EC特异性DICER KO）中缺乏DICER的小鼠是可行的，但产生了产后血管生成反应受损。为了剖析EC中信号转导，基因表达和miRNA之间的关系，我们表明用VEGF处理EC会刺激全局miRNA谱的时间依赖性变化，并表明miRNA簇的成分MiR 17-92可以调节VEGF诱导的细胞生长和变形。此外，我们已经确定了一个特定的miRNA（miR-155），该miRNA调节培养的EC中内皮一氧化氮合酶（ENOS）的水平。因此，我们假设DICER产生内皮miRNA，通过调节重要蛋白质的mRNA水平和/或转化的转化稳定性来调节体内血管生成和血流控制的程度。我们将：1。识别和表征EC中调节的血管生成因子调节的miRNA； 2。定义miR 17-92在血管生成模型中的作用和3。定义miR-155在调节体外和体内调节eNOS功能中的作用。总的来说，这项工作将有助于理解miRNA在EC生物学中的重要性，并洞悉其作为潜在治疗靶标的作用。