Monocyte microRNA155 and atherosclerosis

单核细胞 microRNA155 与动脉粥样硬化

• 批准号: 8208178
• 负责人: Daping Fan
• 金额: $ 17.13万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208178
• 关键词: Adhesions; Arterial Fatty Streak; Atherosclerosis; Base Pairing; Biological Process; Blood Vessels; Cell Differentiation process; Cholesterol; Chronic; Clinical; Complement; Data; Deposition; Development; Diagnosis; Diagnostic; Endothelium; Event; Foam Cells; Functional RNA; Future; Gene Expression; Generations; Heterogeneity; Human; Hyperlipidemia; Immune response; Immunity; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Lead; Lentivirus Vector; Lesion; Ligands; Light; Link; Lipids; Lipoproteins; Measures; Mechanical Stress; Mediating; Messenger RNA; MicroRNAs; Molecular; Mus; Myocardial Infarction; Nature; Pathologic Processes; Patients; Phenotype; Plasma; Play; Prognostic Marker; Regulation; Role; Stress; Stroke; Testing; Therapeutic Agents; Toll-like receptors; Translational Repression; United States; Up-Regulation; atherogenesis; base; cell transformation; clinical practice; clinically significant; design; high reward; high risk; human disease; inflammatory marker; innovation; insight; mRNA Transcript Degradation; macrophage; monocyte; mouse model; novel diagnostics; novel therapeutic intervention; overexpression; oxidized low density lipoprotein; receptor-mediated signaling; tool; vascular inflammation

Project Summary: Atherosclerosis is evoked by both lipid deposition and chronic vascular inflammation, in which monocytes/macrophages play critical roles. The recent identification of heterogeneity of circulating monocytes and lesional macrophages has provided new insights into the mechanism underlying the involvement of monocytes/macrophages in atherogenesis. An emerging notion is that in the presence of systemic pro-atherogenic stress (i.e., hyperlipidemia and inflammation), some circulating monocytes acquire distinct pro-inflammatory phenotypes that prime them to infiltrate the arterial wall and give rise to a pro-inflammatory macrophage subset within the plaque. MicroRNAs (miRs) are short non-coding RNA molecules capable of regulating gene expression by targeting mRNAs, resulting in translational repression or mRNA degradation. They play essential roles in multiple biological and pathological processes, thus emerging as new targets for diagnosis and therapy of several human diseases. One miR, miR155, has been demonstrated to play a crucial role in immune response regulation. Recent studies have shown that miR155 expression in monocytes and macrophages is up-regulated upon stimulation with various ligands for toll-like receptors (TLRs), and it may exaggerate monocyte and macrophage inflammation by targeting several negative regulators of TLR-mediated signaling. While TLRs and their ligands are fundamentally involved in atherogenesis, the contribution of monocyte/macrophage miR155 to atherosclerosis has not been investigated. Our preliminary studies suggest a potential role of monocyte/macrophage miR155 in atherosclerosis, and prompt us to hypothesize that up-regulation of miR155 expression is an integral feature of the pro-atherogenic phenotype of circulating monocytes. Two specific aims are proposed to test this hypothesis. SA1. To test the hypothesis that miR155 expression is up-regulated in circulating monocytes of atherosclerotic mice. We will measure miR155 expression in circulating monocytes using two hypercholesterolemic mouse models, evaluate its correlation with lesion size, plasma lipids, and inflammatory markers, and examine whether miR155 is differentially expressed in circulating monocyte subsets. SA2. To test the hypothesis that increased miR155 expression represents a pro-atherogenic phenotype of monocytes. We will transduce monocytes isolated from mice with lentiviral vectors to introduce miR155 overexpression or inhibition, and test the effects of miR155 manipulation on monocyte adhesion to aortic endothelium, infiltration into intima and foam cell transformation. We will also explore the underlying molecular mechanism.

项目概要： 动脉粥样硬化是由脂质沉积和慢性血管炎症引起的，其中 单核细胞/巨噬细胞起关键作用。循环系统异质性的最新鉴定 单核细胞和病变巨噬细胞的研究为了解 单核细胞/巨噬细胞参与动脉粥样硬化形成。一个新兴的概念是， 全身促动脉粥样硬化应激（即，高脂血症和炎症），一些循环单核细胞 获得不同的促炎表型，使它们渗透动脉壁并引起 致炎性巨噬细胞亚群microRNA（miRs）是一种短的非编码RNA， RNA分子能够通过靶向mRNA调节基因表达，导致翻译 抑制或mRNA降解。它们在多种生物学和病理学中发挥着重要作用 过程，从而成为诊断和治疗几种人类疾病的新靶点。一个miR， miR 155已被证明在免疫应答调节中起关键作用。最近的研究 显示在单核细胞和巨噬细胞中的miR 155表达在用 Toll样受体（TLR）的各种配体，它可能会增加单核细胞和巨噬细胞 通过靶向TLR介导的信号传导的几种负调节剂来治疗炎症。而TLR及其 配体基本上参与动脉粥样硬化的形成，单核细胞/巨噬细胞miR 155对动脉粥样硬化的作用， 动脉粥样硬化尚未被研究。我们的初步研究表明， 单核细胞/巨噬细胞miR 155在动脉粥样硬化中的作用，提示我们假设 miR 155表达是循环单核细胞的促动脉粥样硬化表型的整体特征。 提出了两个具体目标来检验这一假设。SA 1.为了验证miR 155 在动脉粥样硬化小鼠的循环单核细胞中表达上调。我们将测量 使用两种高胆固醇血症小鼠模型，评估循环单核细胞中miR 155的表达， 其与病变大小、血脂和炎症标志物的相关性，并检查miR 155 在循环单核细胞亚群中差异表达。SA 2.为了验证这个假设， 增加的miR 155表达代表单核细胞的促动脉粥样硬化表型。我们将 从具有慢病毒载体的小鼠中分离的单核细胞，以引入miR 155过表达或 抑制，并测试miR 155操作对单核细胞粘附至主动脉内皮的影响， 内膜浸润和泡沫细胞转化。我们还将探索潜在的分子 机制