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 酒精性肝病(ALD)是世界范围内慢性肝病的主要病因之一。 在美国，近50%的肝硬变相关死亡病例。长期饮酒使个人处于一种 酒精性脂肪性肝炎(ASH)、肝硬变、 和肝细胞癌。肝移植是治疗ALD的唯一选择，但供应不足 道德方面的考虑往往会成为障碍。皮质类固醇仍然是ALD唯一可用的治疗方法， 约有60%的患者近期有反应，但无长期生存优势。因此，小说 迫切需要治疗策略。ABL家族的酪氨酸蛋白激酶，其中包括ABL1 (也称为c-ABL)和ABL2(也称为ARG)，将不同的细胞外刺激与信号通路联系起来 它们控制着细胞的生长、存活、入侵、黏附和迁移。然而，ABL激酶在ALD中的作用 之前还没有建立过。最近，我们发现ABL激酶在小鼠肝脏中被激活。 乙醇处理。此外，与正常肝脏相比，ABL激酶在人类ALD样本中也被激活。 这些数据表明，ABL激酶可能在ALD中起作用。为了了解ABL激酶在ALD中的作用， 我们建立了新的肝脏特异性ABL1、ABL2或ABL1/ABL2缺陷小鼠模型。有趣的是，我们发现 ABL2或ABL1/ABL2的缺失而不是ABL1单独可以阻止乙醇诱导的脂肪变性、肝损伤和炎症。 基于这些证据，我们假设酒精激活ABL2促进酒精诱导 脂肪变性、肝脏损伤和炎症。因此，ABL激酶的抑制可能会抑制酒精诱导 脂肪变性、肝脏损伤和炎症。如果这一假设得到证实，我们的结果将表明ABL 激酶抑制剂可能对ALD的治疗有用。这项提议的结果可能会揭示一种新的 酒精诱导的脂肪变性、肝损伤和炎症的机制，并为 开发ALD的新治疗策略。