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Role of gp91phox in Hepatic MF Programming and Alcohol Liver Disease

gp91phox 在肝脏 MF 编程和酒精性肝病中的作用

基本信息

批准号：
9129373
负责人：
Cynthia Ju
金额：
$ 22.35万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9129373
关键词：
Accounting Acute Adrenal Cortex Hormones Affect Aftercare Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Animal Model Anti-Inflammatory Agents Anti-inflammatory Bone Marrow Cells Cessation of life Chimera organism Chronic Cues Data Development Disease Ethanol Genes Goals Heavy Drinking Hepatic Heterogeneity Immune system In Vitro Inflammation Inflammatory Injury Knowledge Kupffer Cells Liver Liver Cirrhosis Liver diseases Metabolic Modeling Molecular Mouse Strains Mus NADPH Oxidase Natural Immunity Pathogenesis Patients Pentoxifylline Phagocytosis Pharmacologic Substance Phenotype Play Population Population Heterogeneity Predisposition Research Risk Factors Role Staging Tissues base cell type chronic liver disease feeding in vivo insight liver inflammation liver injury liver transplantation macrophage mouse model novel therapeutics programs public health relevance research study restoration therapeutic development therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) affects more than 10 million people in the U.S. and accounts for nearly half of liver cirrhosis-associated deaths. A better understanding of the pathogenesis of the disease is necessary to develop new therapies, which are currently quite limited. The innate immune system plays an important role in the pathogenesis of ALD. Macrophages (MΦ) is a major type of cells of the innate immunity, and has emerged as a critical player and therapeutic target in many chronic inflammatory diseases. Evidence suggests that hepatic MΦ s are important in the development and progression of ALD. In patients and animal models, increased numbers of hepatic MΦ are found in all stages of ALD, and factors indicating MΦ activation are elevated. Hepatic MΦ s are a heterogeneous population with diverse phenotype and functions. Aside from resident Kupffer cells (KCs), we recently discovered that chronic ethanol feeding to mice causes the hepatic recruitment of infiltrating MΦ s (IMs), which consist of a pro-inflammatory Ly6Chi subset and an anti- inflammatory, tissue-protective Ly6Clow subset. Phagocytosis of dead cells (efferocytosis) promotes the switching of Ly6Chi IMs to Ly6Clow IMs. Moreover, we found that hepatic MΦ s from gp91phox-/- mice have impaired efferocytosis ability. Interestingly, compared with ethanol-fed WT mice, the ratio of Ly6Chi/Ly6Clow IMs, as well as the degree of liver injury, are significantly higher in gp91phox-/- mice. These results led to our hypothesis that gp91phox, through regulating MΦ efferocytosis, plays a critical role in the programming of tissue- restorative hepatic MΦ s, thereby protecting the liver from ALD. We propose two Specific Aims to examine this hypothesis: (Aim 1), Investigate the protective role of gp91phox in ethanol-induced liver inflammation and injury. The degrees of liver injury and inflammation will be compared between WT and gp91phox-/- mice in two models of ALD. Furthermore, bone marrow chimera experiments will be performed to elucidate the contribution of hepatic MΦs to the increased susceptibility of gp91phox-/- mice to ALD. (Aim 2), Investigate the impact of gp91phox-deletion on efferocytosis-induced programming of hepatic MΦs. Various subpopulations of MΦs will be isolated from the livers of ethanol-fed WT and gp91phox-/- mice. The gene profiles of each population will be compared between the two strains of mice. Moreover, the efferocytosis ability and the impact of efferocytosis on the cell phenotype will be compared in each hepatic MΦ population from WT and gp91phox-/- mice.