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
基本信息
- 批准号:10264782
- 负责人:
- 金额:$ 21.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:ABL1 geneABL2 geneAdhesionsAdrenal Cortex HormonesAffectAlcoholic Liver DiseasesAlcoholic steatohepatitisAlcoholsCell physiologyCessation of lifeCirrhosisDNA DamageDataDevelopmentEthanolEthicsFamilyGene set enrichment analysisGenetic TranscriptionGrowth FactorHepatocyteHumanIndividualInflammationKnock-outKnockout MiceLinkLiverLiver diseasesMediatingMolecularMusNOTCH1 geneOxidative StressPatientsPharmacologyPhenotypePhosphotransferasesPhysiologicalPlayPrimary carcinoma of the liver cellsProtein Tyrosine KinaseRegulationReportingRoleSamplingSignal PathwaySignal TransductionStimulusTestingUnited Statesalcohol abuse therapyalcohol responsebasec-myc Genescell growthchronic alcohol ingestionchronic liver diseasecytokineextracellularhigh riskinhibitor/antagonistkinase inhibitorliver inflammationliver injuryliver transplantationmigrationmouse modelnovelnovel therapeutic interventionoverexpressionresponsetranscriptome sequencingtreatment strategy
项目摘要
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。
项目成果
期刊论文数量(0)
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{{ truncateString('Wei Qiu', 18)}}的其他基金
Defining the role of a novel hexokinase in alcoholic liver disease
定义新型己糖激酶在酒精性肝病中的作用
- 批准号:
10791056 - 财政年份:2023
- 资助金额:
$ 21.92万 - 项目类别:
Molecular mechanisms of focal adhesion kinase in promoting hepatocarcinogenesis
粘着斑激酶促进肝癌发生的分子机制
- 批准号:
10534149 - 财政年份:2015
- 资助金额:
$ 21.92万 - 项目类别:
Molecular mechanisms of focal adhesion kinase in promoting hepatocarcinogenesis
粘着斑激酶促进肝癌发生的分子机制
- 批准号:
10320459 - 财政年份:2015
- 资助金额:
$ 21.92万 - 项目类别: