Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis
酒精引起的肝毒性 - 促胰液素/促胰液素受体轴的影响
基本信息
- 批准号:10457005
- 负责人:
- 金额:$ 53.78万
- 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:2020-09-05 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAlcohol-Induced DisordersAlcoholic HepatitisAlcoholic Liver CirrhosisAlcoholic Liver DiseasesAlcoholic liver damageAlcoholic steatohepatitisAlcoholsAnimal ModelBiliaryCCL2 geneCXCL1 geneCell LineCellsCholestasisCholesterolChronicCirrhosisCommunicationCountryDataDisease ProgressionEpithelial CellsEthanolFibrosisGenesHepaticHepatic Stellate CellHepatobiliaryHepatocyteHepatotoxicityHigh Fat DietHumanIL8 geneImmuneImpairmentIn VitroInfiltrationInflammationInflammatoryInjuryKupffer CellsLeadLinkLiverLiver CirrhosisLiver FibrosisLiver diseasesLongitudinal StudiesMediatingMicroRNAsModelingMorbidity - disease rateMusNational Institute on Alcohol Abuse and AlcoholismNerve Growth FactorsNeurosecretory SystemsPathogenesisPathologyPatientsPharmacologyPhenotypePlayPreventionPrimary carcinoma of the liver cellsProliferatingReactionReceptor SignalingResearchRoleSamplingSecretinSerumTestingTherapeuticUnited StatesVascular Endotheliumalcohol exposureantagonistbile ductcholangiocytechronic liver diseasechronic liver injurycytokineextracellular vesiclesfeedinghuman diseaseinsightintrahepaticliver cell proliferationliver inflammationliver injuryloss of functionmortalitymouse modelnovelpreventproblem drinkerreceptorrecruitresponsesecretin receptorsenescencesimple steatosisstellate celltherapeutic evaluationtherapeutic targettranslational studywestern diet
项目摘要
Alcohol-associated liver disease (ALD) is a leading cause of chronic liver diseases and the predominant
cause of liver-related mortality in Western countries. Patients with ALD may develop a wide spectrum of
liver pathologies from simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), cirrhosis,
and eventually hepatocellular carcinoma. Extensive research has been performed to study the impact of
alcohol on hepatocytes, stellate cells, and immune cells including Kupffer cells in ALD, but little is known
about how alcohol affects biliary epithelial cells (i.e., cholangiocytes), and how biliary damage may
contribute to the early and late stages of ALD pathogenesis. Recent studies have indicated that ductular
reaction occurs in patients with alcoholic hepatitis. We have previously shown in other models of hepatic
damage that the secretin (Sct)/secretin receptor (SR) axis is upregulated and plays a critical role in ductular
reaction/biliary senescence as well as contributes to hepatic fibrosis. Our preliminary data that ALD-induced
ductular reaction, biliary senescence, inflammation, and fibrosis were ameliorated in mice lacking the
Sct/SR axis, indicating a crucial role for the SCT/SR axis during the pathogenesis of ALD. We propose the
novel central hypothesis that the SCT/SR signaling axis is a key for mediating the senescent, profibrogenic
biliary phenotype that contributes to the progression of hepatic inflammatory cell infiltration and subsequent
fibrosis during the course of the pathogenesis of ALD. To test our hypothesis, we will pursue the following
specific aims. In Specific aim #1, we will determine that activation of SCT/SR axis-dependent ductular
reaction and biliary senescence plays a key role in the induction of liver inflammation that drives hepatic
fibrosis during the pathogenesis of ALD. In specific aim #2, we will evaluate if therapeutic inhibition of the
SCT/SR axis can prevent and limit the progression of ALD. Completion of the proposed studies will
elucidate the translational mechanism on the role of SCT/SR axis in the promotion of local and systemic
responses to mediate activation of neuroendocrine/profibrogenic biliary phenotype, biliary senescence,
hepatobiliary inflammation and fibrosis during the progression of ALD.
酒精相关性肝病(ALD)是慢性肝脏疾病的主要原因之一
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Gianfranco D Alpini其他文献
Gianfranco D Alpini的其他文献
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{{ truncateString('Gianfranco D Alpini', 18)}}的其他基金
Regulation of Ductular Reaction by Substance P during Alcohol-induced Liver Injury
P物质对酒精性肝损伤过程中小管反应的调节
- 批准号:
10592570 - 财政年份:2023
- 资助金额:
$ 53.78万 - 项目类别:
Role of Sensory Innervation in High Fat Diet-Induced Hepatotoxicity
感觉神经支配在高脂肪饮食引起的肝毒性中的作用
- 批准号:
10467095 - 财政年份:2022
- 资助金额:
$ 53.78万 - 项目类别:
Role of Sensory Innervation in High Fat Diet-Induced Hepatotoxicity
感觉神经支配在高脂肪饮食引起的肝毒性中的作用
- 批准号:
10596643 - 财政年份:2022
- 资助金额:
$ 53.78万 - 项目类别:
Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis
酒精引起的肝毒性 - 促胰液素/促胰液素受体轴的影响
- 批准号:
10252062 - 财政年份:2020
- 资助金额:
$ 53.78万 - 项目类别:
Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis
酒精引起的肝毒性 - 促胰液素/促胰液素受体轴的影响
- 批准号:
10676118 - 财政年份:2020
- 资助金额:
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9930828 - 财政年份:2019
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