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

• 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
• 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

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.

项目概要 该提案的目标是确定中性粒细胞特异性 NADPH 氧化酶 2 (NOX2) 在酒精中毒中的作用 肝 疾病（ALD）并评估其作为治疗靶标的潜力，影响了超过 1000 万人。 在美国，近一半的肝硬化相关死亡病例是由该病引起的。 ALD 对于开发有效的治疗方法至关重要。中性粒细胞在肝脏中的积累是一个标志。 有证据表明中性粒细胞是 ALD 的关键因素。 调节中性粒细胞功能的分子重要途径需要针对这些细胞进行 ALD 最近发现，NADPH 氧化酶（NOX）2（一种主要的酶）的活性和表达水平。 患有以下疾病的患者的中性粒细胞中的活性氧（ROS）来源显着减少 晚期酒精性肝硬化或酒精性肝炎虽然ROS与炎症有关， 越来越多的证据还表明，NOX2 衍生的 ROS 实际上在限制方面发挥着关键作用，而不是 鉴于 NOX2 的矛盾作用，该提案旨在填补这一空白。 关于 NOX2 是否以及如何调节中性粒细胞功能的知识差距。 我们的初步数据表明，中性粒细胞特异性删除 NOX2 的小鼠发育 慢性加狂饮乙醇治疗后的肝损伤和长期炎症。 释放的 IL-1 水平比 WT 中性粒细胞高得多，这些发现共同得出了我们的假设： 中性粒细胞特异性 NOX2 在限制炎症和促进炎症消退方面发挥着关键作用 我们提出三个具体目标：(1) 阐明其机制。 ALD 期间缺乏 NOX2 的中性粒细胞产生的 IL-1 增加，(2) 研究中性粒细胞的作用 特异性 NOX2 在 ALD 期间炎症消退中的作用，(3) 评估靶向中性粒细胞的潜力 特异性 NOX2 治疗 ALD。