Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis

酒精引起的肝毒性 - 促胰液素/促胰液素受体轴的影响

基本信息

批准号：
10252062
负责人：
Gianfranco D Alpini
金额：
$ 54.05万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-05 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10252062
关键词：
Address Affect Alcohol-Induced Disorders Alcoholic Hepatitis Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcoholic liver damage Alcoholic steatohepatitis Alcohols Animal Model Biliary CCL2 gene CXCL1 gene Cell Line Cells Cholesterol Chronic Cirrhosis Communication Country Data Disease Progression Epithelial Cells Ethanol Fibrosis Genes Hepatic Hepatic Stellate Cell Hepatobiliary Hepatocyte Hepatotoxicity High Fat Diet Human IL8 gene Immune Impairment In Vitro Infiltration Inflammation Inflammatory Injury Kupffer Cells Lead Link Liver Liver Cirrhosis Liver Fibrosis Liver diseases Longitudinal Studies Mediating MicroRNAs Modeling Morbidity - disease rate Mus National Institute on Alcohol Abuse and Alcoholism Nerve Growth Factors Neurosecretory Systems Pathogenesis Pathology Patients Pharmacology Phenotype Play Prevention Primary carcinoma of the liver cells Proliferating Reaction Receptor Signaling Research Role Sampling Secretin Serum Testing Therapeutic United States Vascular Endothelium alcohol exposure bile duct cholangiocyte cholestatic liver disease chronic liver disease chronic liver injury cytokine extracellular vesicles feeding human disease insight intrahepatic liver cell proliferation liver inflammation liver injury loss of function mortality mouse model novel prevent problem drinker receptor recruit response secretin receptor senescence stellate cell therapeutic evaluation therapeutic target translational study western diet

项目摘要

Alcohol-associated liver disease (ALD) is a leading cause of chronic liver diseases and the predominant cause of liver-related mortality in Western countries. Patients with ALD may develop a wide spectrum of liver pathologies from simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), cirrhosis, and eventually hepatocellular carcinoma. Extensive research has been performed to study the impact of alcohol on hepatocytes, stellate cells, and immune cells including Kupffer cells in ALD, but little is known about how alcohol affects biliary epithelial cells (i.e., cholangiocytes), and how biliary damage may contribute to the early and late stages of ALD pathogenesis. Recent studies have indicated that ductular reaction occurs in patients with alcoholic hepatitis. We have previously shown in other models of hepatic damage that the secretin (Sct)/secretin receptor (SR) axis is upregulated and plays a critical role in ductular reaction/biliary senescence as well as contributes to hepatic fibrosis. Our preliminary data that ALD-induced ductular reaction, biliary senescence, inflammation, and fibrosis were ameliorated in mice lacking the Sct/SR axis, indicating a crucial role for the SCT/SR axis during the pathogenesis of ALD. We propose the novel central hypothesis that the SCT/SR signaling axis is a key for mediating the senescent, profibrogenic biliary phenotype that contributes to the progression of hepatic inflammatory cell infiltration and subsequent fibrosis during the course of the pathogenesis of ALD. To test our hypothesis, we will pursue the following specific aims. In Specific aim #1, we will determine that activation of SCT/SR axis-dependent ductular reaction and biliary senescence plays a key role in the induction of liver inflammation that drives hepatic fibrosis during the pathogenesis of ALD. In specific aim #2, we will evaluate if therapeutic inhibition of the SCT/SR axis can prevent and limit the progression of ALD. Completion of the proposed studies will elucidate the translational mechanism on the role of SCT/SR axis in the promotion of local and systemic responses to mediate activation of neuroendocrine/profibrogenic biliary phenotype, biliary senescence, hepatobiliary inflammation and fibrosis during the progression of ALD.

酒精相关性肝病（ALD）是慢性肝病的主要原因，也是导致慢性肝病的主要原因。是西方国家肝脏相关死亡的原因。 ALD 患者可能会出现多种症状肝脏病理从单纯性脂肪变性到酒精性脂肪性肝炎 (ASH)、酒精性肝炎 (AH)、肝硬化、并最终发展为肝细胞癌。已经进行了广泛的研究来研究其影响酒精对 ALD 中肝细胞、星状细胞和免疫细胞（包括库普弗细胞）的影响，但人们知之甚少关于酒精如何影响胆道上皮细胞（即胆管细胞），以及胆道损伤如何可能有助于 ALD 发病机制的早期和晚期阶段。最近的研究表明，导管酒精性肝炎患者会出现这种反应。我们之前已经在其他肝模型中展示过促胰液素 (Sct)/促胰液素受体 (SR) 轴上调并在导管中发挥关键作用反应/胆道衰老以及导致肝纤维化。我们的初步数据表明 ALD 诱导缺乏这些的小鼠的胆管反应、胆道衰老、炎症和纤维化得到改善 Sct/SR 轴，表明 SCT/SR 轴在 ALD 发病机制中发挥着至关重要的作用。我们建议新的中心假设认为 SCT/SR 信号轴是介导衰老、促纤维化的关键胆管表型有助于肝脏炎症细胞浸润和随后的进展 ALD 发病过程中的纤维化。为了检验我们的假设，我们将追求以下目标具体目标。在具体目标#1中，我们将确定 SCT/SR 轴依赖性导管的激活反应和胆道衰老在诱导肝脏炎症中起关键作用，从而驱动肝脏 ALD 发病过程中的纤维化。在具体目标#2中，我们将评估是否治疗性抑制 SCT/SR轴可以预防和限制ALD的进展。完成拟议的研究将阐明 SCT/SR 轴在促进局部和全身作用中的转化机制对介导神经内分泌/促纤维化胆道表型激活、胆道衰老的反应， ALD 进展过程中的肝胆炎症和纤维化。