Mechanism of neutrophilic NCF1 in alcohol-associated liver disease pathogenesis
中性粒细胞NCF1在酒精相关性肝病发病机制中的作用机制
基本信息
- 批准号:10723321
- 负责人:
- 金额:$ 14.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-08 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAlcoholic HepatitisAlcoholic Liver DiseasesAnimal ModelAutomobile DrivingBasic ScienceBilirubinBindingBiogenesisCell CommunicationCell modelCellsCellular StressClinicalComplexDataDiseaseDockingEthanolGenerationsGenesHepaticHepatitisHepatocyteHomeostasisImmuneInflammasomeInflammation MediatorsInflammatory ResponseKnock-outKnowledgeLinkLiverLiver diseasesMAP Kinase GeneMediatingMedicalMembraneMicroRNAsModelingMolecularMorbidity - disease rateMultienzyme ComplexesMusMyeloid CellsNADPNeutrophil InfiltrationOxidasesOxidative StressOxidative Stress InductionPathogenesisPathway interactionsPatientsPatternPhagocytesPhenotypePhosphotransferasesPlayProductionProteinsPublic HealthReactive Oxygen SpeciesResearch ActivityRoleSerumSeverity of illnessSignal PathwayTranslational ResearchUnited StatesUp-Regulationalcohol use disordercell injuryend stage liver diseaseexperimental studyextracellularextracellular vesicleshepatocyte injuryimprovedintercellular communicationinterpatient variabilityintrahepaticliver injurymortalitynanoscaleneutrophilp38 Mitogen Activated Protein Kinasesystemic inflammatory responsetargeted treatmenttissue injurytranscriptome sequencingvesicular release
项目摘要
Project Summary
Alcohol-associated liver disease (ALD) is a complex disease and represents a spectrum of histopathological
changes in the liver. Accumulating evidence suggests that multiple types of immune cells are involved in the
pathogenesis of alcohol-associated hepatitis (AH), particularly neutrophils. However, the mechanisms
underlying neutrophils in mediating AH pathogenesis are not well understood. Our exploratory experiments
had led to an important and clinical observation on the inter-patient variability and two distinct patterns of
hepatic neutrophil infiltration. Our data also indicated that higher level of hepatic parenchymal neutrophils was
associated with AH disease severity. The key question we would like to address in this application is how
neutrophils drives disease severity and mediates liver injury in ALD. Mechanistically, neutrophils, as an innate
inflammatory response, mediates tissue injury by producing inflammatory mediators and reactive oxygen
species (ROS). ROS production in neutrophils is regulated by the multi-meric transmembrane enzyme
complex, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Among them, the NCF1
gene, which encodes the phagocytic oxidase (phox) unit p47phox, is predominantly expressed in neutrophils
and plays an important role in controlling ROS production in neutrophils. Our data suggested that miR-223,
the most abundant neutrophilic miRNA, may be a downstream target of NCF1 and its induction ameliorates
alcohol-induced liver injury. In specific aim#1, we will determine the molecular mechanism on the inhibition of
neutrophilic miR-223 by NCF1. Our data and planned experiments in specific aim#1 will expand our current
knowledge on the signaling pathway in the neutrophils, neutrophilic Ncf1-induced oxidative stress, and miR-
223 expression. The next important question to address is how the inhibition of miR-223 by NCF1-induced
oxidative stress leads to hepatocyte injury. In specific aim #2, we will determine the downstream crosstalk
between neutrophil-induced ROS generation and hepatocytes via extracellular vesicles (EVs) leading to
alcohol-induced liver injury. Taken together, we have developed animal and cellular models to mechanistically
examine the roles of neutrophils in ALD pathogenesis. Understanding the mechanism linking neutrophils to
ALD pathogenesis is of importance; this will pave a way for the discovery of potential targeted therapy for
patients with ALD.
项目总结
项目成果
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