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

这个补充项目的首要主题是增加家长奖的新信息， 导致酒精性肝病（ALD）时IEC细胞外囊泡（EV）的改变。我们将重点关注ω6 PUFAs和肠道微生物群调节的exmiRNAs。具体来说，我们将研究ω6 PUFAs如何刺激 通过TLR 4/STAT 3信号传导产生肠道EV以及这些事件在发展中的后果 ALD通过肠-肝轴。新的体外和体内方法将用于解决作用机制 目的是确定新的干预目标。我们认为ω6多不饱和脂肪酸诱导了 肠道微生物群，这有助于肠道衍生EV的miRNA谱的变化。我们特别 我们提出TLR 4/STAT 3激活的细胞外miRNAs的产生是激活细胞内miRNAs的关键。 巨噬细胞在ALD中ω6 PUFAs诱导的慢性炎症期间。基于我们已发表的工作， 其他初步数据，这项建议将测试假设，ω6多不饱和脂肪酸调节生产的肠道 通过TLR 4/STAT 3信号转导，启动巨噬细胞之间的串扰， 肝细胞ALD。此外，我们将确定补充ω3 PUFAs是否与饮食相关， 携带炎性miRNAs抑制剂的纳米颗粒在ALD中具有潜在的治疗意义。这些 将在以下具体目标中检验假设：目标1：确定ω6 PUFA调节的作用 酒精诱导的肝脏炎症中的肠道EV。目的2：确定IEC miRNAs的改变是否通过 TLR 4/STAT 3调节影响ALD中ω6 PUFAs诱导的肝脏炎症和损伤的严重程度 .

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. .