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The role of intestinal gp130 in alcohol-associated liver disease

肠道 gp130 在酒精相关性肝病中的作用

基本信息

批准号：
10742561
负责人：
Ana Cristina Llorente Izquierdo
金额：
$ 41.48万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10742561
关键词：
Accounting Alcohol abuse Alcohol consumption Alcohol dependence Alcoholic Liver Diseases Bacteria Bacterial Translocation Biopsy Cell Wall Cells Cessation of life Chronic Complex Diet Down-Regulation Duodenum Engineering Epithelial Cells Ethanol Growth Heavy Drinking Human IL6ST gene Immune response Infection Inflammation Interleukin Activation Interleukin-11 Interleukin-6 Interleukins Intervention Intestinal permeability Intestines JAK1 gene LIF gene Lectin Ligands Liver Liver diseases Lymphoid Cell Maintenance Mediating Medical Modeling Molecular Mucosal Immune System Mus Natural regeneration Organoids Pathogenesis Pathogenicity Pathway interactions Patients Permeability Phosphorylation Play Pre-Clinical Model Predisposition Prevention Preventive Preventive therapy Process Production Proteins Regenerating islet derived protein 3-Gamma Regenerative response Research Resistance Risk Factors Role Signal Induction Signal Pathway Signal Transduction Signal Transduction Pathway Small Intestines Stat3 protein Steatohepatitis Technology Testing Therapeutic Therapeutic Intervention Time Tissues alcohol consequences alcohol exposure alcohol prevention alcohol use disorder antagonist antimicrobial antimicrobial peptide cardiotrophin 1 cell injury chronic liver disease cytokine cytokine receptor gp130 design disability dysbiosis effective therapy feeding gain of function gut bacteria gut microbiota gut-liver axis healing innovation interleukin-22 intestinal epithelium intestinal homeostasis islet liver inflammation loss of function microbial microbial composition microbiome research microbiota mouse model novel oncostatin M overexpression pathogen pre-clinical prevent receptor receptor binding response therapeutic evaluation

项目摘要

Project Summary/Abstract The most prominent consequence of alcohol use disorder is alcohol-associated liver disease (ALD). Alcohol abuse is associated with intestinal dysbiosis, bacterial overgrowth, increased gut permeability, and bacterial translocation to the liver, promoting liver inflammation. This insult to the liver, exacerbates ALD. The gut-liver axis plays a crucial role on the pathogenesis of ALD. Within this axis the intestinal microbiota composition, the mucosal immune system and intestinal specialized cells are fundamental regulators. These components are disturbed during ALD. Alcohol consumption decreases the pool of interleukin (IL)-22 secreting type 3 innate lymphoid cells (ILC3). IL-22 leads to the production of antimicrobial regenerating islet-derived protein 3 (REG3) lectins mediated by activation of the signal transducer and activator of transcription 3 (STAT3) signaling in the intestine. Antimicrobial REG3 lectins regulate the intestinal microbial composition and prevent from bacterial translocation. Expression of REG3 lectins is reduced in small intestines of ethanol-fed mice and in the duodenum of patients with alcohol use disorder (AUD). Therefore, we hypothesize that restoring the expression of intestinal REG3 lectins would be an effective therapy for patients with ALD. Phosphorylation of STAT3-REG3 axis also occurs through activation of the IL-6 signal transducer (IL6ST/gp130) coreceptor. We preliminarily determined the protective role of overactive intestinal gp130 in ethanol-induced liver disease in mice. gp130 pathway signals through four different signaling transduction pathways, among them the most prominent is gp130-STAT3 pathway. Hence, we aim to define the exact signaling transduction cassette involved in the preventive role of gp130 in ethanol-induced liver disease and define the use of an engineered gp130 receptor ligand as a novel translational interventional strategy to prevent ALD. To explore the proposed hypothesis, aim 1 will investigate whether gp130-STAT3-REG3 signaling cassette is involved in the prevention against ethanol-induced liver disease. This approach proposes to use ethanol-fed mice overexpressing active intestinal gp130 but with specific deletion of intestinal STAT3. It will assess the role of gp130-STAT3-REG3 axis in the prevention of ethanol-mediated dysregulation of microbiota composition, intestinal permeability, bacterial translocation to the liver, and steatohepatitis. Aim 2 will define whether the use of a novel engineered chimeric gp130 ligand is effective as a therapy to prevent ethanol-induced liver disease preclinically in mice and test its intestinal effects in human small intestinal organoids from AUD patients. The proposed study will characterize the role of gp130-STAT3-REG3 axis in preclinical models of ethanol- induced liver disease and in patients with alcohol use disorder using cutting edge microbiomics and state-of-the- art technology. The proposed intervention will find innovative strategies to prevent alcohol-associated liver disease in patients.

项目总结/摘要酒精使用障碍最突出的后果是酒精相关性肝病（ALD）。醇滥用与肠道生态失调、细菌过度生长、肠道渗透性增加和细菌感染有关。易位到肝脏，促进肝脏炎症。这种对肝脏的损害会加重ALD。肠肝轴在酒精性肝脏疾病的发病机制中起着至关重要的作用。在该轴内，肠道微生物群组成，粘膜免疫系统和肠道特化细胞是基本的调节器。这些组件在ALD期间受到干扰。饮酒减少白细胞介素（IL）-22分泌型3先天性淋巴样细胞（ILC 3）。IL-22导致抗微生物再生胰岛衍生蛋白3（REG 3）的产生通过激活信号转导子和转录激活子3（STAT 3）信号转导介导的凝集素，肠子抗微生物REG 3凝集素调节肠道微生物组成并防止细菌感染易位REG 3凝集素的表达在乙醇喂养的小鼠的小肠和十二指肠中减少酒精使用障碍（AUD）患者。因此，我们假设，肠REG 3凝集素可能是ALD患者的有效治疗方法。 STAT 3-REG 3轴的磷酸化也通过IL-6信号转导子的激活而发生（IL 6ST/gp 130）辅助受体。我们初步确定了过度活跃的肠道gp 130在酒精诱导的小鼠肝脏疾病。gp 130信号通路通过四种不同的信号转导途径途径，其中最突出的是gp 130-STAT 3途径。因此，我们的目标是定义精确的 gp 130在酒精性肝病中的预防作用并定义了工程化的GP 130受体配体作为新的翻译干预策略的用途预防ALD。为了探索所提出的假设，目的1将研究gp 130-STAT 3-REG 3信号盒是否是参与预防乙醇引起的肝病。该方法建议使用乙醇进料过表达活性肠gp 130但特异性缺失肠STAT 3的小鼠。它将评估 gp 130-STAT 3-REG 3轴在预防乙醇介导的微生物群组成失调中的作用，肠通透性、细菌移位至肝脏和脂肪性肝炎。目标2将定义是否使用一种新的工程嵌合gp 130配体是有效的治疗，以防止乙醇诱导的肝脏疾病在小鼠中进行临床前试验，并测试其在来自AUD患者的人小肠类器官中的肠道作用。该研究将描述gp 130-STAT 3-REG 3轴在乙醇临床前模型中的作用。诱导的肝病和酒精使用障碍患者使用尖端微生物学和国家的艺术技术。拟议的干预措施将找到预防酒精相关性肝脏的创新策略患者的疾病。