ROLE OF MICRORNA-155 IN MACROPHAGE FUNCTION AND ATHEROSCLEROSIS

MICRORNA-155 在巨噬细胞功能和动脉粥样硬化中的作用

• 批准号: 8167798
• 负责人: Daping Fan
• 金额: $ 10万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167798
• 关键词: Arterial Fatty Streak; Atherosclerosis; Base Pairing; Biological Process; Cholesterol; Chronic; Computer Retrieval of Information on Scientific Projects Database; Deposition; Development; Diagnosis; Disease; Foam Cells; Functional RNA; Funding; Gene Expression; Genes; Grant; Human; Immune response; Immunity; In Vitro; Inflammation; Inflammation Process; Inflammatory; Inflammatory Response; Institution; Ligands; Lipids; Lipopolysaccharides; Mediating; MicroRNAs; Molecular; Mus; Oncogenic; Peritoneal Macrophages; Play; Regulation; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Subfamily lentivirinae; Testing; Translational Repression; United States National Institutes of Health; atherogenesis; cancer cell differentiation; cytokine; human disease; mRNA Transcript Degradation; macrophage; overexpression; oxidized low density lipoprotein; three-dimensional modeling; toll-like receptor 4

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Atherosclerosis is both a lipid deposit disease and a chronic inflammation process. A vicious cycle between cholesterol accumulation and inflammatory response exists in macrophages and directly presents the partnership of cholesterol and inflammation in atherosclerosis. Oxidized LDL (oxLDL) and Toll-like receptor 4 (TLR4) on macrophages trigger an inflammatory signaling in which many details are unclear. MicroRNAs (miRs) are short non-coding RNA molecules capable of regulating gene expression post-transcriptionally through base pairing with mRNAs, resulting in either translational repression or mRNA degradation. They are estimated to regulate up to a third of all human genes and play critical roles in multiple biological processes, including cell differentiation, cancer transformation and immunity development, thus emerging as new targets for the diagnosis and therapy of human diseases. One miR, miR155 has been demonstrated to be oncogenic and to play a crucial role in immune response regulation. Recent studies have revealed that miR155 expression in macrophages is up-regulated upon stimulation with multiple ligands for TLRs. While TLRs and their ligands are fundamentally involved in atherogenesis, the relationship between macrophage miR155 and atherosclerosis has not been investigated. Our preliminary studies suggest that: 1) miR155 is up-regulated in mouse peritoneal macrophages by oxidized low density lipoprotein (oxLDL) and lipopolysaccharide (LPS) in a TLR4-dependent manner; macrophage miR155 expression positively correlates with the expression of pro-inflammatory cytokines under various conditions; 2) Lentivirus-mediated overexpression of miR155 enhances macrophage inflammatory response to oxLDL and LPS, and impairs macrophage cholesterol efflux; 3) MiR155 expression is increased in mouse atherosclerotic lesions. In order to further investigate the role of macrophage miR155 in atherogenesis and develop strategies to halt atherosclerosis through manipulating macrophage miR155 expression, we propose to test our central hypothesis that macrophage miR155 promotes atherosclerosis through modulating macrophage function. We propose three objectives: 1. To test the hypothesis that miR155 is up-regulated in atherosclerotic lesion macrophages; 2. To investigate the molecular mechanism of miR155 function in macrophages; 3. To test the hypothesis in an in vitro 3D model that miR155 promotes macrophages foam cell formation and inflammation.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 动脉粥样硬化既是一种脂质沉积性疾病，又是一种慢性炎症过程。巨噬细胞中存在胆固醇蓄积和炎症反应之间的恶性循环，直接反映了动脉粥样硬化中胆固醇和炎症的伙伴关系。巨噬细胞表面的氧化低密度脂蛋白(OxLDL)和Toll样受体4(TLR4)触发了一种炎症信号，其中许多细节尚不清楚。MicroRNAs(MiRs)是一种短小的非编码RNA分子，能够通过与mRNAs的碱基配对在转录后调控基因的表达，导致翻译抑制或mRNA降解。据估计，它们调控多达三分之一的人类基因，并在包括细胞分化、癌症转化和免疫发展在内的多种生物过程中发挥关键作用，从而成为人类疾病诊断和治疗的新靶点。一种miR，miR155已被证明是致癌的，并在免疫反应调节中发挥关键作用。最近的研究表明，巨噬细胞中miR155的表达在TLRs的多个配体刺激下上调。虽然TLRs及其配体基本上参与了动脉粥样硬化的形成，但巨噬细胞miR155与动脉粥样硬化的关系尚未被研究。我们的初步研究表明：1)氧化低密度脂蛋白(OxLDL)和脂多糖(LPS)以TLR4依赖的方式上调小鼠腹腔巨噬细胞miR155的表达；在不同条件下，巨噬细胞miR155的表达与促炎细胞因子的表达呈正相关；2)慢病毒介导的miR155过表达增强了巨噬细胞对oxLDL和LPS的炎症反应，并损害了巨噬细胞的胆固醇外流；3)在小鼠动脉粥样硬化病变中，miR155的表达增加。为了进一步研究巨噬细胞miR155在动脉粥样硬化形成中的作用，并开发通过调控巨噬细胞miR155表达来抑制动脉粥样硬化的策略，我们建议验证我们的中心假设，即巨噬细胞miR155通过调节巨噬细胞功能促进动脉粥样硬化。我们提出了三个目标：1.验证miR155在动脉粥样硬化病变中巨噬细胞上调的假说；2.研究miR155在巨噬细胞中作用的分子机制；3.在体外三维模型中验证miR155促进巨噬细胞泡沫细胞形成和炎症的假说。