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Intestinal epithelial cells-derived exosomal miRNAs regulate liver inflammation in obesity

肠上皮细胞来源的外泌体 miRNA 调节肥胖中的肝脏炎症

基本信息

批准号：
9385034
负责人：
Zhong-Bin Deng
金额：
$ 23.1万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-14 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9385034
关键词：
Address Affect Automobile Driving Cell physiology Cells Chronic Colitis Colon Carcinoma Consumption Data Development Diet Dietary Supplementation Distant Eicosapentaenoic Acid Encapsulated Epithelial Epithelial Cells Event Fatty acid glycerol esters Foundations Future Goals Hepatic Hepatocyte High Fat Diet Hypoxia Immune Immune signaling Impairment In Vitro Infiltration Inflammation Inflammatory Inflammatory disease of the intestine Injury Intervention Intestines Investigation Lead Link Linoleic Acids Liver Mediating Mediator of activation protein MicroRNAs Modeling Molecular Mucins Mucous Membrane N-3 polyunsaturated fatty acid Natural Killer Cells Nonesterified Fatty Acids Obese Mice Obesity Pathogenicity Pathway interactions Patients Permeability Play Polyunsaturated Fatty Acids Production Property Proteins Publishing Recruitment Activity Regulation Role STAT3 gene Severities Signal Transduction Testing Therapeutic Therapeutic Intervention Tumor Angiogenesis Ulcer Ulcerative Colitis Up-Regulation Work antimicrobial base exosome extracellular gastrointestinal epithelium in vivo inhibitor/antagonist interest liver development liver inflammation liver injury macrophage migration nanoparticle nanovesicle non-alcoholic fatty liver novel nutrition octadecadienoic acid overexpression prevent translational study

项目摘要

The overarching theme of this project is to explore the mechanisms that lead to liver inflammation/injury in obesity. We will focus on extracellular miRNAs of intestinal epithelial cells (IECs) and macrophages. Specifically, we will examine how polyunsaturated fatty acids mediated-intestinal inflammation stimulates the production of extracellular miRNAs from IECs and the consequences of these events. Novel in vitro and in vivo approaches will be used to address mechanisms of action with the goal of identifying new targets for intervention. We propose that dietary n-6 polyunsaturated fatty acids (n-6 PUFAs) promote liver inflammation and injury via IEC-derived exosomes. We specifically propose that Stat3-activated extracellular miRNAs are the key to the accumulation/polarization of macrophages in liver in obese mice. Based on our published work and other preliminary data, this proposal will test the hypothesis that the n-6 PUFAs regulate the production of extracellular miRNAs from intestinal epithelial cells through Stat3 signaling, which initiates a crosstalk among macrophages, NK cells and hepatocytes in liver. Moreover, we will determine whether diet fat-associated nanoparticles carrying miR-155 inhibitor have potential therapeutic implications in obesity. These hypotheses will be tested in the following Specific Aims: Aim 1: Determine whether IEC-derived extracellular miRNAs regulated by the n-6 PUFAs/Stat3 pathway are specific mediators of NFALD development and progression. Aim 2: Determine whether alteration of IEC miRNAs via STAT3 modulation affects the severity of HFD-induced liver inflammation and injury in obesity. Following the successful completion of the above Specific Aims, our novel studies will (i) validate Stat3-activated extracellular miRNAs is directly relevant to the accumulation/polarization of hepatic macrophages in obesity, and (ii) provide a foundation for future mechanistic investigation of the regulation of diet fat and extracellular miRNA in obesity therapy.

该项目的首要主题是探索导致肥胖症肝脏炎症/损伤的机制。我们将重点关注肠上皮细胞 (IEC) 和巨噬细胞的细胞外 miRNA。具体来说，我们将研究多不饱和脂肪酸介导的肠道炎症如何刺激产生来自 IEC 的细胞外 miRNA 以及这些事件的后果。新颖的体外和体内方法将用于解决行动机制问题，以期确定新的干预目标。我们提出膳食 n-6 多不饱和脂肪酸 (n-6 PUFA) 会促进肝脏炎症和损伤通过 IEC 衍生的外泌体。我们特别提出 Stat3 激活的细胞外 miRNA 是关键肥胖小鼠肝脏中巨噬细胞的积累/极化。基于我们已发表的工作和其他初步数据，该提案将检验 n-6 PUFA 调节生产的假设通过 Stat3 信号传导从肠上皮细胞中提取细胞外 miRNA，从而启动细胞间的串扰肝脏中的巨噬细胞、NK 细胞和肝细胞。此外，我们将确定饮食脂肪是否与携带 miR-155 抑制剂的纳米颗粒对肥胖症具有潜在的治疗意义。这些假设将在以下具体目标中进行测试：目标 1：确定 IEC 衍生的细胞外 miRNA 是否受 n-6 PUFA/Stat3 途径调节的 NFALD 发展的特定介质进展。目标 2：确定通过 STAT3 调制改变 IEC miRNA 是否会影响 HFD 引起的肥胖肝脏炎症和损伤的严重程度。继顺利完成上述具体目标，我们的新研究将 (i) 验证 Stat3 激活的细胞外 miRNA 是否直接相关肥胖症中肝巨噬细胞的积累/极化，以及（ii）为未来奠定基础肥胖治疗中膳食脂肪和细胞外 miRNA 调节的机制研究。