Gut extracellular vesicles promote alcohol-induced liver injury via TLR4-regulated miRNAs

肠道细胞外囊泡通过 TLR4 调节的 miRNA 促进酒精引起的肝损伤

• 批准号: 9804746
• 负责人: Zhong-Bin Deng
• 金额: $ 15.4万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9804746
• 关键词: Address; Affect; Alcoholic Liver Diseases; Alcohols; Antigens; Attenuated; Automobile Driving; Award; Cells; Chronic; Colon Carcinoma; Consumption; Data; Development; Diet; Distant; Epithelial; Epithelial Cells; Event; Goals; Grant; Hepatic; Hepatocyte; High Fat Diet; Immune; Immune signaling; Immunotherapy; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory disease of the intestine; Injury; Intervention; Intestinal permeability; Intestines; Kupffer Cells; Lead; Link; Linoleic Acids; Liver; Liver diseases; Macrophage Activation; Mediating; MicroRNAs; Molecular; Outcome; Parents; Pathogenicity; Patients; Play; Polyunsaturated Fatty Acids; Production; Proteins; Publishing; Regulation; Role; STAT3 gene; Severities; Signal Transduction; TLR4 gene; Testing; Therapeutic; Therapeutic Intervention; Ulcerative Colitis; Work; antimicrobial; base; dysbiosis; exosome; extracellular; extracellular vesicles; fatty acid supplementation; gut microbiota; gut-liver axis; improved; in vivo; inhibitor/antagonist; interest; liver development; liver inflammation; liver injury; macrophage; microbial; migration; nanoparticle; nanovesicle; non-alcoholic fatty liver disease; novel; nutrition; overexpression; prevent; response; therapeutic target; translational study; vesicular release

The overarching theme of this supplementary project is to add the new information of parent award that nutrition lead to the changes of extracellular vesicles (EVs) of IECs in alcoholic liver disease (ALD). We will focus on ω6 PUFAs and gut microbiota-regulated exmiRNAs. Specifically, we will examine how ω6 PUFAs stimulate the production of gut EVs through TLR4/STAT3 signaling and the consequences of these events in the development of ALD via gut-liver axis. 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 ω6 PUFAs induce the dysbiosis of gut microbiota, which contribute to the changes in the miRNAs profile of gut-derived EVs. We specifically propose that TLR4/STAT3-activated extracelluar miRNAs production is the key to the activation of macrophages during ω6 PUFAs-induced chronic inflammation in ALD. Based on our published work and other preliminary data, this proposal will test the hypothesis that ω6 PUFAs regulate the production of gut extracellular miRNAs through TLR4/STAT3 signaling, which initiates a crosstalk among macrophages and hepatocytes in ALD. Moreover, we will determine whether supplement of ω3 PUFAs with diet-associated nanoparticles carrying inflammatory miRNAs inhibitor have potential therapeutic implications in ALD. These hypotheses will be tested in the following Specific Aims: Aim 1: Determine the role of ω6 PUFAs-regulated gut EVs in alcohol-induced liver inflammation. Aim 2: Determine whether alteration of IEC miRNAs via TLR4/STAT3 modulation affects the severity of ω6 PUFAs-induced liver inflammation and injury in ALD. .

该补充项目的总体主题是增加营养家长奖的新信息 导致酒精性肝病(ALD)时IEC胞外小泡(EVS)的变化。我们将重点介绍ω6 多不饱和脂肪酸和肠道微生物区系调控的exmiRNAs。具体来说，我们将研究ω6多不饱和脂肪酸如何刺激 通过TLR4/STAT3信号产生肠道EVS及其在发育过程中的后果 经胃肠-肝轴的ALD。新的体外和体内方法将被用来解决作用机制 目标是确定新的干预目标。我们认为ω-6多不饱和脂肪酸可诱导 肠道微生物区系，这有助于肠源性电动汽车miRNAs图谱的变化。我们特别指出 提出TLR4/STAT3激活的胞外miRNAs的产生是激活的关键 ω-6多不饱和脂肪酸诱导酒精性肝病慢性炎症过程中巨噬细胞的变化基于我们已发表的工作和 其他初步数据，这项提议将检验ω6多不饱和脂肪酸调节肠道生产的假设 通过TLR4/STAT3信号转导的胞外miRNAs，从而在巨噬细胞和 ALD中的肝细胞。此外，我们将确定补充ω3多不饱和脂肪酸是否与饮食相关 携带炎性miRNAs抑制剂的纳米颗粒对ALD具有潜在的治疗意义。这些 假说将在以下具体目标中进行检验：目标1：确定ω6多不饱和脂肪酸调节的作用 肠道EVS在酒精性肝脏炎症中的作用。目标2：确定IEC miRNAs是否通过 TLR4/STAT3信号转导通路影响ω-6多不饱和脂肪酸诱导的酒精性肝病肝脏炎症和损伤程度。 。