miR-181b, endothelial cells, and vascular inflammation

miR-181b、内皮细胞和血管炎症

• 批准号: 9383086
• 负责人: MARK W FEINBERG
• 金额: $ 63.71万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383086
• 关键词: ADORA2A gene; Adenosine; Adhesives; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Bioluminescence; Blood Vessels; Cardiovascular system; Cell Adhesion Molecules; Cell Communication; Cell physiology; Characteristics; Chronic; Coronary Arteriosclerosis; Deletion Mutation; Development; Disease; Disease Progression; Endothelial Cells; Foundations; Functional disorder; Gene Expression; Gene Targeting; Genetic Transcription; Goals; Grant; Human; Hyperlipidemia; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Insulin Resistance; Knockout Mice; Leukocytes; Ligands; Link; MAPK8 gene; Mediating; Methotrexate; MicroRNAs; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; NF-kappa B; NFKB Signaling Pathway; Nodal; Obesity; Pathway interactions; Peripheral Vascular Diseases; Process; Property; Proto-Oncogene Proteins c-akt; Publishing; Regulation; Reporter Genes; Risk Factors; Rodent; Role; Signal Pathway; Signal Transduction; Societies; Stimulus; Stroke; Therapeutic; Thrombosis; Untranslated RNA; Vascular Cell Adhesion Molecule-1; Vascular Endothelium; atherogenesis; atherothrombosis; cell type; chemokine; clinically relevant; crosslinking and immunoprecipitation sequencing; cytokine; human subject; immunoregulation; in vivo; inhibitor/antagonist; insight; insulin signaling; intravital microscopy; molecular imaging; mortality; nanoparticle; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; response; transcriptome sequencing; vascular inflammation

Endothelial cell (EC) activation and dysfunction have been linked to a variety of chronic vascular inflammatory disease states including insulin resistance (IR), obesity, and atherosclerosis—the major cause of morbidity and mortality in Western Societies. Proinflammatory cytokines and proatherogenic risk factors such as hyperlipidemia activate key signaling pathways such as NF-kB and MEKK/JNK and decrease protective ones such as AKT/eNOS signaling, an effect that confers pro-adhesive and pro-thrombotic properties to ECs. Therefore, suppressing the inflammatory response in the vascular endothelium may provide a novel therapeutic approach to limit IR/obesity, and atherothrombosis. MicroRNAs (miRNAs) are small, single-stranded, non-coding RNAs capable of repressing gene expression at the post-transcriptional level and are involved in a variety of pathophysiological processes including the regulation of immune and inflammatory responses. During this grant period, we identified miR-181b as a nodal regulator of endothelial cell quiescence through its regulatory effects on two major signaling pathways – NF-kB and AKT/eNOS, and have uncovered novel targets for therapy. Preliminary and published observations now identify endothelial miR-181b as a critical determinant of systemic inflammation, obesity/IR, and atherogenesis. Furthermore, our studies highlight the relevance of microRNA-dependent targets in response to ligand-specific signaling in ECs–an emerging concept in the microRNA field. Moreover, we demonstrate that methotrexate (MTX), a clinically relevant therapy that suppresses endothelial activation, can function in a miR-181b- dependent manner. These observations provide the foundation for the central hypothesis that endothelial miR- 181b, via inhibitory effects on NF-κB and MEKK/JNK and inductive effects on AKT/eNOS signaling, regulates systemic vascular inflammation, IR/obesity, and atherosclerosis. To better understand the precise role of miR- 181b in stimuli-specific regulation of EC activation, three aims are proposed. In Aim1, we will delineate the molecular basis for miR-181b's ability to inhibit endothelial NF-κB and MEKK/JNK and induce AKT/eNOS pathways in response to divergent stimuli. In Aim2, we will determine the effect of altered endothelial miR-181b expression on obesity/insulin resistance and atherothrombosis. In Aim3, we will explore the molecular mechanisms by which methotrexate (MTX) rescues miR-181b expression in ECs, and we will determine whether the anti-inflammatory effects of MTX are miR-181b-dependent. The results of these studies will provide insights regarding miR-181b-mediated control of endothelial activation and the functional consequences of miR-181b sufficiency and deficiency on insulin resistance and atherogenesis. Furthermore, studies exploring the link between miR-181b and MTX may provide insights that can be exploited for therapeutic gain in the treatment of a broad spectrum of chronic inflammatory disorders.

内皮细胞（EC）的激活和功能障碍与多种慢性血管炎性疾病有关。 疾病状态包括胰岛素抵抗（IR）、肥胖和动脉粥样硬化-发病的主要原因， 西方社会的死亡率。促炎细胞因子和促动脉粥样硬化危险因素，如 高脂血症激活关键信号通路如NF-kB和MEKK/JNK并降低保护性通路 例如AKT/eNOS信号传导，这是一种赋予EC促粘附和促血栓形成特性的作用。 因此，抑制血管内皮中的炎症反应可能提供新的治疗方法。 限制IR/肥胖和动脉粥样硬化血栓形成的治疗方法。 microRNAs（miRNAs）是一种小的单链非编码RNA，能够抑制基因表达， 转录后水平，并参与多种病理生理过程，包括 调节免疫和炎症反应。在此资助期间，我们将miR-181 b鉴定为一个节点， 通过对两个主要信号通路NF-κ B的调节作用调节内皮细胞静止 和AKT/eNOS，并发现了新的治疗靶点。目前已发表的初步意见 鉴定内皮miR-181 b作为全身性炎症、肥胖/IR和动脉粥样硬化形成关键决定因素。 此外，我们的研究强调了microRNA依赖性靶点与配体特异性靶点的相关性。 EC中的信号传导-microRNA领域的新兴概念。此外，我们证明，甲氨蝶呤， (MTX)，一种抑制内皮活化的临床相关疗法，可以在miR-181 b- 依赖的方式。这些观察结果为内皮细胞miR-1表达的核心假设提供了基础。 181 B通过抑制NF-κB和MEKK/JNK以及诱导AKT/eNOS信号传导，调节 全身性血管炎症、IR/肥胖和动脉粥样硬化。为了更好地了解miR-1的确切作用， 181 b在EC激活的刺激特异性调节中，提出了三个目标。在目标1中，我们将描述 miR-181 B抑制内皮细胞NF-κB和MEKK/JNK并诱导AKT/eNOS的分子基础 对不同刺激的反应。在Aim 2中，我们将确定改变内皮miR-181 b的作用， 肥胖/胰岛素抵抗和动脉粥样硬化血栓形成的表达。在Aim 3中，我们将探索分子 甲氨蝶呤（MTX）拯救EC中miR-181 b表达的机制，我们将确定 MTX的抗炎作用是否依赖于miR-181 b。这些研究的结果将 提供了关于miR-181 b介导的内皮激活控制和功能性 miR-181 b充足和缺乏对胰岛素抵抗和动脉粥样硬化形成的影响。此外，委员会认为， 探索miR-181 b和MTX之间联系的研究可能提供可用于 在治疗广谱慢性炎性疾病中的治疗增益。