Defining the Role of ABL Kinases in Alcoholic Liver Disease

定义 ABL 激酶在酒精性肝病中的作用

• 批准号: 10264782
• 负责人: Wei Qiu
• 金额: $ 21.92万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264782
• 关键词: ABL1 gene; ABL2 gene; Adhesions; Adrenal Cortex Hormones; Affect; Alcoholic Liver Diseases; Alcoholic steatohepatitis; Alcohols; Cell physiology; Cessation of life; Cirrhosis; DNA Damage; Data; Development; Ethanol; Ethics; Family; Gene set enrichment analysis; Genetic Transcription; Growth Factor; Hepatocyte; Human; Individual; Inflammation; Knock-out; Knockout Mice; Link; Liver; Liver diseases; Mediating; Molecular; Mus; NOTCH1 gene; Oxidative Stress; Patients; Pharmacology; Phenotype; Phosphotransferases; Physiological; Play; Primary carcinoma of the liver cells; Protein Tyrosine Kinase; Regulation; Reporting; Role; Sampling; Signal Pathway; Signal Transduction; Stimulus; Testing; United States; alcohol abuse therapy; alcohol response; base; c-myc Genes; cell growth; chronic alcohol ingestion; chronic liver disease; cytokine; extracellular; high risk; inhibitor/antagonist; kinase inhibitor; liver inflammation; liver injury; liver transplantation; migration; mouse model; novel; novel therapeutic intervention; overexpression; response; transcriptome sequencing; treatment strategy

Abstract Alcoholic liver disease (ALD) is one of the primary causes of chronic liver disease worldwide and accounts for nearly 50% of cirrhosis associated deaths in the United States. Chronic alcohol use places individuals at a high risk for advanced and largely irreversible liver diseases including alcoholic steatohepatitis (ASH), cirrhosis, and hepatocellular carcinoma. Liver transplantation is the only curative option for ALD but insufficient supplies and ethical considerations often come in the way. Corticosteroids remain the only available therapy for ALD, with a short-term response in about 60% of patients, but no long-term survival advantage. Consequently, novel therapeutic strategies are desperately needed. The ABL family of tyrosine protein kinases, which includes ABL1 (also known as c-ABL) and ABL2 (also known as ARG), link diverse extracellular stimuli to signaling pathways that control cell growth, survival, invasion, adhesion, and migration. However, the role of ABL kinases in ALD has not previously been established. Recently, we found that ABL kinases are activated in mouse liver upon ethanol treatment. In addition, ABL kinases are also activated in human ALD samples compared to normal livers. These data suggest that ABL kinases might play a role in ALD. To understand the role of ABL kinases in ALD, we generated novel liver-specific Abl1, Abl2 or Abl1/Abl2-deficient mouse models. Intriguingly, we found that deletion of Abl2 or Abl1/Abl2 but not Abl1 alone blocked ethanol-induced steatosis, liver injury and inflammation. Based on these pieces of evidences, we hypothesize that ABL2 activation by alcohol promotes alcohol-induced steatosis, liver injury, and inflammation. Accordingly, ABL kinases inhibition may suppress alcohol-induced steatosis, liver injury, and inflammation. If this hypothesis were confirmed, our results would suggest that ABL kinase inhibitors might be useful for treating ALD. The results of this proposal could potentially reveal a novel mechanism for alcohol-induced steatosis, liver injury, and inflammation and provide the groundwork for the development of novel treatment strategies for ALD.

摘要