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

基本信息

批准号：
9753076
负责人：
Zhong-Bin Deng
金额：
$ 18.29万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753076
关键词：
Address Affect Alcoholic Liver Diseases Alcohols Antigens Attenuated Automobile Driving Cell physiology Cells Chronic Colitis Colon Carcinoma Data Development Diet Distant Epithelial Epithelial Cells Event Foundations Future Goals Hepatic Hepatocyte Hypoxia Immune Immune signaling Immunotherapy Impairment In Vitro Inflammation Inflammatory Inflammatory disease of the intestine Injury Intervention Intestinal permeability Intestines Investigation Kupffer Cells Lead Link Liver Liver diseases Macrophage Activation Mediating MicroRNAs Molecular Myeloid Cells Outcome Pathogenicity Patients Play Preventive Production Proteins Publishing Regulation Role Severities Signal Transduction TLR4 gene Testing Therapeutic Tumor Angiogenesis Ulcerative Colitis Work antimicrobial base chronic alcohol ingestion exosome extracellular extracellular vesicles gut microbiota gut-liver axis immunoregulation improved in vivo inhibitor/antagonist interest liver development liver inflammation liver injury macrophage microbial microorganism antigen migration mouse model nanoparticle nanovesicle novel nutrition overexpression prevent recruit response therapeutic target translational study vesicular release

项目摘要

The overarching theme of this project is to explore the mechanisms that lead to immune regulation of alcoholic liver disease (ALD). We will focus on extracellular vesicles (EVs) of gut and hepatic macrophages. Specifically, we will examine how microbial antigen stimulates the production of gut EVs through TLR4 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 gut-derived EVs regulate the accumulation and polarization of hepatic macrophages during alcohol-induced chronic inflammation via TLR4 signaling. We specifically propose that TLR4-activated extracelluar miRNAs production is the key to the activation of macrophages. Based on our published work and other preliminary data, this proposal will test the hypothesis that microbial antigen regulates the production of gut extracellular miRNAs through TLR4 signaling, which initiates a crosstalk among macrophages and hepatocytes in ALD. Moreover, we will determine whether 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 TLR4-regulated gut EVs on alcohol-induced liver inflammation and injury. Aim 2: Determine whether alteration of IEC miRNAs via TLR4 modulation affects the severity of alcohol-induced liver inflammation and injury in ALD. Following the successful completion of the above Specific Aims, our novel studies will (i) validate TLR4 activated EVs is directly relevant to the activation of hepatic macrophages in ALD, (ii) define the preventive potential of TLR4-extracellular miRNAs axis in a mouse model of ALD and (iii) provide a foundation for future mechanistic investigation of gut EVs and extracellular miRNA in ALD therapy.

该项目的总体主题是探索导致酒精饮料免疫调节的机制肝病（ALD）。我们将专注于肠道和肝巨噬细胞的细胞外囊泡（EV）。具体来说，我们将研究微生物抗原如何通过TLR4信号传导刺激肠道电动汽车的产生这些事件在通过肠叶轴发展中的后果。新颖的体外和体内方法将用于解决行动机制，目的是确定新目标进行干预。我们提出肠道衍生的电动汽车调节肝巨噬细胞的积累和极化酒精引起的慢性炎症通过TLR4信号传导。我们明确提出了TLR4激活外部miRNA的产生是巨噬细胞激活的关键。根据我们发表的工作和其他初步数据，该提案将检验微生物抗原调节生产的假设通过TLR4信号传导肠道外miRNA的肠外miRNA，这引发了巨噬细胞之间的串扰 Ald中的肝细胞。此外，我们将确定是否携带炎症的饮食相关纳米颗粒 miRNA抑制剂在ALD中具有潜在的治疗意义。这些假设将在以下测试具体目的：目标1：确定TLR4调节的肠道电动汽车在酒精引起的肝脏炎症上的作用和受伤。目标2：确定通过TLR4调制的IEC miRNA的改变是否会影响严重性酒精引起的肝脏炎症和ALD损伤。成功完成以上具体目的，我们的新研究将（i）验证TLR4激活的EV与肝的激活直接相关 ALD中的巨噬细胞，（ii）定义了在小鼠模型中TLR4-纤维细胞miRNA轴的预防潜力 ALD和（iii）为对ALD中肠道电动汽车和细胞外miRNA的未来机械研究奠定了基础治疗。