权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10457005
负责人：
Gianfranco D Alpini
金额：
$ 53.78万
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/10457005
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 Cholestasis 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 antagonist bile duct cholangiocyte 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 simple steatosis 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）是慢性肝脏疾病的主要原因之一