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/巨噬细胞发挥着关键作用。最近发现循环的异质性 单核细胞和病变巨噬细胞提供了对潜在机制的新见解 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，在存在的情况下 系统性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 获得独特的促炎表型，使它们能够渗透动脉壁并产生 斑块内的促炎巨噬细胞亚群。 MicroRNA (miR) 是短非编码 RNA 分子能够通过靶向 mRNA 来调节基因表达，从而产生翻译 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，从而成为多种人类疾病诊断和治疗的新靶点。一个 miR， miR155已被证明在免疫反应调节中发挥着至关重要的作用。最近的研究有 表明单核细胞和巨噬细胞中 miR155 的表达在刺激后上调 Toll 样受体 (TLR) 的各种配体，它可能会夸大单核细胞和巨噬细胞 通过针对 TLR 介导的信号传导的多个负调节因子来抑制炎症。虽然 TLR 及其 配体从根本上参与动脉粥样硬化形成，单核细胞/巨噬细胞 miR155 对动脉粥样硬化的贡献 动脉粥样硬化尚未得到研究。我们的初步研究表明， 单核细胞/巨噬细胞 miR155 在动脉粥样硬化中的表达，促使我们假设 miR155 表达是循环单核细胞促动脉粥样硬化表型的一个重要特征。 提出了两个具体目标来检验这一假设。 SA1。检验 miR155 的假设 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的 miR155 表达 其与病变大小、血脂和炎症标志物的相关性，并检查 miR155 是否 在循环单核细胞亚群中差异表达。 SA2。为了检验以下假设 miR155 表达增加代表单核细胞的促动脉粥样硬化表型。我们将 用慢病毒载体转导从小鼠分离的单核细胞以引入 miR155 过表达或 抑制，并测试 miR155 操作对单核细胞与主动脉内皮粘附的影响， 浸润内膜并发生泡沫细胞转化。我们还将探索潜在的分子 机制。