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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 动脉粥样硬化既是脂质沉积疾病，也是慢性炎症过程。巨噬细胞中存在胆固醇积累和炎症反应之间的恶性循环，并直接提出了动脉粥样硬化中胆固醇和炎症的伙伴关系。巨噬细胞上氧化的LDL（OXLDL）和类似Toll样受体4（TLR4）触发了炎症信号传导，其中许多细节尚不清楚。 microRNA（miRS）是短的非编码RNA分子，能够通过与mRNA配对在转录后调节基因表达，从而导致翻译抑制或mRNA降解。据估计，它们可以调节所有人类基因的三分之一，并在多种生物学过程中起关键作用，包括细胞分化，癌症转化和免疫发展，从而成为人类疾病诊断和治疗的新靶标。一种miR，miR155已被证明是致癌的，并且在免疫反应调节中起着至关重要的作用。最近的研究表明，在用多种配体用于TLR时，巨噬细胞中的miR155表达被上调。尽管TLR及其配体从根本上参与了动脉粥样硬化，但巨噬细胞miR155与动脉粥样硬化之间的关系尚未研究。我们的初步研究表明：1）miR155在小鼠腹膜巨噬细胞中通过氧化的低密度脂蛋白（OXLDL）和脂多糖（LPS）以TLR4依赖性方式上调；巨噬细胞miR155表达与在各种条件下的促炎细胞因子的表达呈正相关。 2）慢病毒介导的miR155的过表达增强了对OXLDL和LPS的巨噬细胞炎症反应，并损害巨噬细胞胆固醇外排； 3）小鼠动脉粥样硬化病变中的miR155表达增加。为了进一步研究巨噬细胞miR155在动脉粥样硬化中的作用，并通过操纵巨噬细胞mir155表达来制定阻止动脉粥样硬化的策略，我们建议测试巨噬细胞miR155通过调节巨噬细胞功能来促进动脉粥样硬化的中心假设。我们提出了三个目标：1。检验以下假设：Mir155在动脉粥样硬化病变巨噬细胞中上调； 2。研究巨噬细胞中miR155功能的分子机制； 3。在体外3D模型中测试MiR155促进巨噬细胞泡沫细胞形成和炎症的假设。