Mechanism of neutrophilic NCF1 in alcohol-associated liver disease pathogenesis

中性粒细胞NCF1在酒精相关性肝病发病机制中的作用机制

• 批准号: 10723321
• 负责人: JING MA
• 金额: $ 14.72万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-08 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723321
• 关键词: Address; Alcoholic Hepatitis; Alcoholic Liver Diseases; Animal Model; Automobile Driving; Basic Science; Bilirubin; Binding; Biogenesis; Cell Communication; Cell model; Cells; Cellular Stress; Clinical; Complex; Data; Disease; Docking; Ethanol; Generations; Genes; Hepatic; Hepatitis; Hepatocyte; Homeostasis; Immune; Inflammasome; Inflammation Mediators; Inflammatory Response; Knock-out; Knowledge; Link; Liver; Liver diseases; MAP Kinase Gene; Mediating; Medical; Membrane; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Multienzyme Complexes; Mus; Myeloid Cells; NADP; Neutrophil Infiltration; Oxidases; Oxidative Stress; Oxidative Stress Induction; Pathogenesis; Pathway interactions; Patients; Pattern; Phagocytes; Phenotype; Phosphotransferases; Play; Production; Proteins; Public Health; Reactive Oxygen Species; Research Activity; Role; Serum; Severity of illness; Signal Pathway; Translational Research; United States; Up-Regulation; alcohol use disorder; cell injury; end stage liver disease; experimental study; extracellular; extracellular vesicles; hepatocyte injury; improved; intercellular communication; interpatient variability; intrahepatic; liver injury; mortality; nanoscale; neutrophil; p38 Mitogen Activated Protein Kinase; systemic inflammatory response; targeted treatment; tissue injury; transcriptome sequencing; vesicular release

Project Summary Alcohol-associated liver disease (ALD) is a complex disease and represents a spectrum of histopathological changes in the liver. Accumulating evidence suggests that multiple types of immune cells are involved in the pathogenesis of alcohol-associated hepatitis (AH), particularly neutrophils. However, the mechanisms underlying neutrophils in mediating AH pathogenesis are not well understood. Our exploratory experiments had led to an important and clinical observation on the inter-patient variability and two distinct patterns of hepatic neutrophil infiltration. Our data also indicated that higher level of hepatic parenchymal neutrophils was associated with AH disease severity. The key question we would like to address in this application is how neutrophils drives disease severity and mediates liver injury in ALD. Mechanistically, neutrophils, as an innate inflammatory response, mediates tissue injury by producing inflammatory mediators and reactive oxygen species (ROS). ROS production in neutrophils is regulated by the multi-meric transmembrane enzyme complex, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Among them, the NCF1 gene, which encodes the phagocytic oxidase (phox) unit p47phox, is predominantly expressed in neutrophils and plays an important role in controlling ROS production in neutrophils. Our data suggested that miR-223, the most abundant neutrophilic miRNA, may be a downstream target of NCF1 and its induction ameliorates alcohol-induced liver injury. In specific aim#1, we will determine the molecular mechanism on the inhibition of neutrophilic miR-223 by NCF1. Our data and planned experiments in specific aim#1 will expand our current knowledge on the signaling pathway in the neutrophils, neutrophilic Ncf1-induced oxidative stress, and miR- 223 expression. The next important question to address is how the inhibition of miR-223 by NCF1-induced oxidative stress leads to hepatocyte injury. In specific aim #2, we will determine the downstream crosstalk between neutrophil-induced ROS generation and hepatocytes via extracellular vesicles (EVs) leading to alcohol-induced liver injury. Taken together, we have developed animal and cellular models to mechanistically examine the roles of neutrophils in ALD pathogenesis. Understanding the mechanism linking neutrophils to ALD pathogenesis is of importance; this will pave a way for the discovery of potential targeted therapy for patients with ALD.

项目总结