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.
项目概要
酒精相关性肝病(ALD)是一种复杂的疾病,代表了一系列组织病理学特征
肝脏的变化。越来越多的证据表明多种类型的免疫细胞参与了
酒精相关性肝炎(AH)的发病机制,特别是中性粒细胞。然而,这些机制
中性粒细胞在介导 AH 发病机制中的作用尚不清楚。我们的探索性实验
导致了对患者间变异性和两种不同模式的重要临床观察
肝脏中性粒细胞浸润。我们的数据还表明,肝实质中性粒细胞水平较高
与 AH 疾病的严重程度相关。我们想在这个应用程序中解决的关键问题是如何
中性粒细胞会导致 ALD 疾病严重程度并介导肝损伤。从机制上讲,中性粒细胞作为一种先天的
炎症反应,通过产生炎症介质和活性氧介导组织损伤
物种(ROS)。中性粒细胞中 ROS 的产生受多聚跨膜酶的调节
复合物,烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶(NOX)。其中,NCF1
编码吞噬氧化酶 (phox) 单位 p47phox 的基因主要在中性粒细胞中表达
并在控制中性粒细胞中ROS的产生中发挥重要作用。我们的数据表明 miR-223,
最丰富的中性粒细胞 miRNA,可能是 NCF1 的下游靶点及其诱导改善
酒精引起的肝损伤。在具体目标#1中,我们将确定抑制的分子机制
NCF1 影响中性粒细胞 miR-223。我们在特定目标#1 中的数据和计划实验将扩展我们当前的
中性粒细胞信号通路、中性粒细胞 Ncf1 诱导的氧化应激和 miR-
223 表达。下一个要解决的重要问题是NCF1如何诱导miR-223的抑制
氧化应激导致肝细胞损伤。在具体目标#2中,我们将确定下游串扰
中性粒细胞诱导的 ROS 生成和肝细胞之间通过细胞外囊泡 (EV) 产生
酒精引起的肝损伤。总而言之,我们开发了动物和细胞模型,以机械方式
检查中性粒细胞在 ALD 发病机制中的作用。了解中性粒细胞与
ALD 发病机制很重要;这将为发现潜在的靶向治疗铺平道路
酒精性肝病(ALD)患者。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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