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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.

该项目的主要主题是探索肥胖导致肝脏炎症/损伤的机制。我们将重点研究肠上皮细胞(IECS)和巨噬细胞的细胞外miRNAs。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来自IECS的胞外miRNAs以及这些事件的后果。新的体外和体内研究方法将用于处理行动机制，目的是确定新的干预目标。我们提出膳食n-6多不饱和脂肪酸(n-6 PUFAs)促进肝脏炎症和损伤通过IEC衍生的外切体。我们特别提出，STAT3激活的胞外miRNAs是关键对肥胖小鼠肝脏巨噬细胞积聚/极化的影响。基于我们已发表的工作和其他初步数据，这一提议将检验n-6多不饱和脂肪酸调节细胞外的miRNAs通过STAT3信号从肠上皮细胞中释放出来，这在肝内巨噬细胞、NK细胞和肝细胞。此外，我们将确定饮食中的脂肪是否与携带miR-155抑制剂的纳米颗粒对肥胖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来源的细胞外miRNAs 受n-6PUFAs/STAT3通路调控的是NFALD发生和发展的特异性介质进步。目的2：确定通过STAT3调制改变IEC miRNAs是否影响肥胖者高脂饲料所致肝脏炎症和损伤的严重程度。继成功完成在上述特定目标上，我们的新研究将(I)验证STAT3激活的胞外miRNAs与肥胖时肝巨噬细胞的蓄积/极化，以及(Ii)为未来的研究提供基础肥胖治疗中饮食脂肪和细胞外miRNA调节的机制研究。