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Role of neutrophil-specific NOX2 in alcohol-induced liver injury

中性粒细胞特异性NOX2在酒精性肝损伤中的作用

基本信息

批准号：
10621545
负责人：
Cynthia Ju
金额：
$ 43.24万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621545
关键词：
Accounting Adoptive Transfer Adrenal Cortex Hormones Affect Agonist Alcoholic Hepatitis Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcohols Attenuated Cells Cessation of life Chronic Data Defect Development Disease Ethanol Exhibits Goals Impairment Infection Inflammasome Inflammation Inflammatory Inflammatory Response Knowledge Liver Liver Cirrhosis Macrophage Mitochondria Modeling Molecular Mus NADPH Oxidase National Institute on Alcohol Abuse and Alcoholism Pathogenesis Pathway interactions Patients Pentoxifylline Persons Pharmacologic Substance Phase Phenotype Play Predisposition Production Reactive Oxygen Species Resolution Role Serine Protease Source effective therapy inflammatory marker insight liver inflammation liver injury liver transplantation molecular marker neutrophil novel therapeutic development therapeutic target

项目摘要

PROJECT SUMMARY The goal of this proposal is to define the role of neutrophil-specific NADPH oxidase 2 (NOX2) in alcoholic liver disease(ALD) and to evaluate its potential as a therapeutic target. ALD affectsmore than 10 million people in the U.S. and accounts for nearly half of liver cirrhosis-associated deaths. Understanding the pathogenesis of ALD is imperative for the development of effective therapies. Neutrophil accumulation in the liver is a hallmark for ALD. Evidence suggests that neutrophils are a key contributor to ALD. However, better understanding of molecular pathways important in regulating neutrophil functions is required to target these cells for ALD treatment. It is recently revealed that the activity and expression levels of NADPH oxidase (NOX)2, a major source of reactive oxygen species (ROS), were dramatically reduced in neutrophils from patients with advanced alcoholic cirrhosis or alcoholic hepatitis. Although ROS has been associated with inflammation, mounting evidence also suggests that NOX2-derived ROS actually plays a critical role in limiting, rather than promoting, inflammatory responses. Given the paradoxical role of NOX2, this proposal aims to fill the knowledge gaps regarding whether and how NOX2 regulates neutrophil functions. Our preliminary data demonstrate that mice with neutrophil-specific deletion of NOX2 develop exacerbated liver injury and prolonged inflammation after chronic plus binge ethanol treatment. NOX2-deficient neutrophils release much higher levels of IL-1 than WT-neutrophils. Together these findings led to our hypothesis that neutrophil-specific NOX2 plays a critical role in limiting inflammation and promoting resolution of inflammation during ALD. We propose three Specific Aims to (1) elucidate the mechanism accounting for increased IL-1 production by NOX2-deficient neutrophils during ALD, (2) investigate the role of neutrophil- specific NOX2 in the resolution of inflammation during ALD, (3) evaluate the potential of targeting neutrophil- specific NOX2 to treat ALD.

项目总结