ROLE OF MICRORNA-155 IN MACROPHAGE FUNCTION AND ATHEROSCLEROSIS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 动脉粥样硬化既是一种脂质存款疾病，也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，并直接呈现了动脉粥样硬化中胆固醇和炎症反应的伙伴关系。巨噬细胞上的氧化低密度脂蛋白（oxLDL）和Toll样受体4（TLR 4）触发炎症信号传导，其中许多细节尚不清楚。microRNA（miRs）是一类短的非编码RNA分子，通过与mRNA的碱基配对，在转录后调节基因表达，导致翻译抑制或mRNA降解。据估计，它们调节多达三分之一的人类基因，并在多种生物过程中发挥关键作用，包括细胞分化，癌症转化和免疫发育，从而成为诊断和治疗人类疾病的新靶点。miR 155是一种致癌的miR，在免疫应答调节中起着至关重要的作用。最近的研究表明，miR 155在巨噬细胞中的表达在用TLR的多种配体刺激后上调。尽管TLR及其配体基本上参与动脉粥样硬化形成，但巨噬细胞miR 155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）氧化低密度脂蛋白（oxLDL）和脂多糖（LPS）以TLR 4依赖的方式上调小鼠腹腔巨噬细胞miR 155的表达，在各种条件下，巨噬细胞miR 155的表达与促炎细胞因子的表达呈正相关; 2）慢病毒介导的miR 155过表达增强巨噬细胞对oxLDL和LPS的炎症反应，并损害巨噬细胞胆固醇流出; 3）小鼠动脉粥样硬化病变中MiR 155表达增加。为了进一步研究巨噬细胞miR 155在动脉粥样硬化形成中的作用，并开发通过操纵巨噬细胞miR 155表达来阻止动脉粥样硬化的策略，我们建议测试我们的中心假设，即巨噬细胞miR 155通过调节巨噬细胞功能来促进动脉粥样硬化。我们提出三个目标：1。验证miR 155在动脉粥样硬化病变巨噬细胞中上调的假设; 2.探讨miR 155在巨噬细胞中发挥作用的分子机制; 3.在体外3D模型中检验miR 155促进巨噬细胞泡沫细胞形成和炎症的假设。

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.