Synergistic actions by multiple Toll-like receptors in alcoholic liver disease
多个 Toll 样受体在酒精性肝病中的协同作用
基本信息
- 批准号:8515903
- 负责人:
- 金额:$ 33.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-09-20 至 2015-08-31
- 项目状态:已结题
- 来源:
- 关键词:ActivinsAddressAdultAlcohol abuseAlcoholic Liver DiseasesAlcoholsAnimalsAscitesBacterial DNABindingBloodBlood - brain barrier anatomyBone MarrowBone Morphogenetic ProteinsBrainBrain InjuriesCD14 AntigenCell CommunicationCell DeathCellsCessation of lifeChimera organismChronicCirrhosisCoculture TechniquesDNADevelopmentDown-RegulationEncephalitisEndothelial CellsEndotoxinsEpithelialEthanolFibrosisFunctional disorderGenotypeGoalsHealthcareHeavy DrinkingHepaticHepatic Stellate CellHepatocyteImmuneIn VitroInflammationInflammation MediatorsInflammatoryInflammatory ResponseInfusion proceduresInjuryIntakeInterleukin-1IntestinesKnockout MiceKupffer CellsLigandsLinkLipidsLipopolysaccharidesLiverLiver CirrhosisLiver FailureLiver FibrosisMeasuresMediatingMediator of activation proteinMembraneModelingMolecularMorbidity - disease rateMusMutant Strains MiceOrganPathogenesisPathway interactionsPatientsPermeabilityPlasmaPopulationPortal HypertensionPortal vein structurePredispositionPrimary carcinoma of the liver cellsProductionReactive Oxygen SpeciesReceptor SignalingRodentRoleSeveritiesSignal TransductionSourceStagingSteatohepatitisTLR4 geneTNF geneTestingTight JunctionsTissuesToll-like receptorsUnited Statesbasecare burdencell typecytokinefeedingin vivoinhibitor/antagonistinsightmacrophagemortalityproblem drinkerpublic health relevanceresponsetoll-like receptor 4
项目摘要
DESCRIPTION (provided by applicant): Chronic alcohol abuse is the major cause of cirrhosis and liver failure in adult patients in the United States. Alcoholic liver disease in patients progresses from steatosis to steatohepatitis, fibrosis, and cirrhosis. The current concept is that chronic alcoholic intake increases intestinal permeability that leads to an elevation of endotoxin (lipopolysaccharide, LPS) levels in the portal vein. Increased endotoxin via the portal vein stimulates Kupffer cells through Toll-like receptor (TLR) 4, a receptor for LPS, which promotes hepatic inflammation resulting in alcoholic liver injury. Not only LPS, but also bacterial DNA levels in blood and ascites are elevated in patients with alcoholic-induced liver cirrhosis. Bacterial DNA is recognized by TLR9 that is widely expressed in immune cells including Kupffer cells, resident macrophages in the liver. On the other hand, we have recently shown that TLR4 directly activates hepatic stellate cells (HSCs) in hepatic fibrosis. We hypothesize that excessive alcohol intake disrupts intestinal epithelial barrier leads to translocation of intestinal microflora- derived LPS and bacterial DNA into the liver. LPS and bacterial DNA activate TLR4 and TLR9, respectively, expressed in Kupffer cells and HSCs, which in turn produce inflammatory and fibrogenic mediators, resulting in alcoholic steatosis, steatohepatitis (ASH) and fibrosis. Synergistic interaction between TLR4 and TLR9, and increased sensitivity of hepatocytes to cell death might further exacerbate the degrees of ASH and fibrosis. Upon ethanol treatment, Kupffer cells in the liver produce inflammatory cytokines, which could be associated with systemic organ injury including brain injury. Based on these hypotheses, the aims of this proposal are: Aim #1: To determine the role of TLR4 on the activation of Kupffer cells and HSCs in ASH; TLR4-bone marrow chimera will be generated and treated with intragastric ethanol feeding. Brain injury and intestinal permeability will be assessed. Aim #2: To determine the role of TLR9 in ASH; The responsible cell types for TLR9 in the liver will be assessed in ASH models. Aim #3: To determine the synergistic actions by TLR4 and TLR9 in Kupffer cells and HSCs. Aim #4: To determine whether the sensitivity of hepatocytes to cell death is increased in ASH. We will test these specific aims using the continuous intragastric ethanol feeding model. The proposed study will provide insight into the molecular mechanism underlying the role of multiple TLR signaling in Gut- Liver-Brain interaction in alcohol-induced pathogenesis.
PUBLIC HEALTH RELEVANCE: Alcoholic steatohepatitis represents a massive health care burden worldwide. The goal of this study is to investigate whether TLR4 and TLR9 synergistically promote alcoholic steatohepatitis and subsequent brain injury. The results from this study will provide the potential targeting for the therapy of alcohol-induced organ pathogenesis including steatohepatitis and brain injury.
描述(由申请人提供):长期酗酒是美国成年患者肝硬化和肝功能衰竭的主要原因。患者的酒精性肝病从脂肪变性进展为脂肪性肝炎、纤维化和肝硬化。目前的概念是,长期饮酒会增加肠道通透性,导致门静脉内毒素(脂多糖,LPS)水平升高。通过门静脉增加的内毒素会通过 Toll 样受体 (TLR) 4(一种 LPS 受体)刺激 Kupffer 细胞,从而促进肝脏炎症,导致酒精性肝损伤。酒精性肝硬化患者不仅 LPS 升高,血液和腹水中的细菌 DNA 水平也升高。细菌 DNA 被 TLR9 识别,TLR9 广泛表达于免疫细胞中,包括库普弗细胞(肝脏中的常驻巨噬细胞)。另一方面,我们最近发现TLR4在肝纤维化过程中直接激活肝星状细胞(HSC)。我们假设过量饮酒会破坏肠上皮屏障,导致肠道微生物群衍生的 LPS 和细菌 DNA 易位到肝脏中。 LPS和细菌DNA分别激活Kupffer细胞和HSC中表达的TLR4和TLR9,进而产生炎症和纤维化介质,导致酒精性脂肪变性、脂肪性肝炎(ASH)和纤维化。 TLR4 和 TLR9 之间的协同相互作用以及肝细胞对细胞死亡的敏感性增加可能会进一步加剧 ASH 和纤维化的程度。乙醇治疗后,肝脏中的库普弗细胞会产生炎症细胞因子,这可能与包括脑损伤在内的全身器官损伤有关。基于这些假设,本提案的目的是: 目标#1:确定 TLR4 在 ASH 中 Kupffer 细胞和 HSC 激活中的作用;将产生TLR4-骨髓嵌合体并用胃内乙醇饲喂进行处理。将评估脑损伤和肠道通透性。目标#2:确定 TLR9 在 ASH 中的作用;肝脏中负责 TLR9 的细胞类型将在 ASH 模型中进行评估。目标#3:确定 TLR4 和 TLR9 在 Kupffer 细胞和 HSC 中的协同作用。目标#4:确定 ASH 中肝细胞对细胞死亡的敏感性是否增加。我们将使用连续胃内乙醇喂养模型来测试这些具体目标。拟议的研究将深入了解多重 TLR 信号传导在酒精诱导的发病机制中肠-肝-脑相互作用中的作用的分子机制。
公共卫生相关性:酒精性脂肪性肝炎在全世界范围内造成了巨大的医疗负担。本研究的目的是调查 TLR4 和 TLR9 是否协同促进酒精性脂肪性肝炎和随后的脑损伤。这项研究的结果将为酒精引起的器官发病机制(包括脂肪性肝炎和脑损伤)的治疗提供潜在的靶点。
项目成果
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{{ truncateString('EKIHIRO SEKI', 18)}}的其他基金
A human Liver-on-a-Chip model for studying alcohol-associated liver disease
用于研究酒精相关肝病的人类芯片肝脏模型
- 批准号:
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$ 33.25万 - 项目类别:
Project 2 - Fatty Liver Predisposes to Metastasis: Role of Hepatic Stellate Cells
项目 2 - 脂肪肝易于转移:肝星状细胞的作用
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10558481 - 财政年份:2020
- 资助金额:
$ 33.25万 - 项目类别:
Project 2 - Fatty Liver Predisposes to Metastasis: Role of Hepatic Stellate Cells
项目 2 - 脂肪肝易于转移:肝星状细胞的作用
- 批准号:
10331758 - 财政年份:2020
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$ 33.25万 - 项目类别:
Role of TLR7 in progression and treatment of alcoholic hepatitis
TLR7在酒精性肝炎进展和治疗中的作用
- 批准号:
10190743 - 财政年份:2018
- 资助金额:
$ 33.25万 - 项目类别:
Role of TLR7 in progression and treatment of alcoholic hepatitis
TLR7在酒精性肝炎进展和治疗中的作用
- 批准号:
10442533 - 财政年份:2018
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$ 33.25万 - 项目类别:
Alcohol enhances colon cancer liver metastasis via cancer-associated fibroblasts
酒精通过癌症相关成纤维细胞增强结肠癌肝转移
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9331372 - 财政年份:2017
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Synergistic Actions By Multiple Toll-Like Receptors in Alcoholic Liver Disease
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9025358 - 财政年份:2015
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$ 33.25万 - 项目类别:
Extracellular Matrix Regulates Hepatic Stellate Cell Activation and Fibrosis
细胞外基质调节肝星状细胞活化和纤维化
- 批准号:
9753207 - 财政年份:2011
- 资助金额:
$ 33.25万 - 项目类别:
LPS binding to TLR4 regulates hepatic stellate cell activation and fibrosis
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8039827 - 财政年份:2011
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$ 33.25万 - 项目类别:
LPS binding to TLR4 regulates hepatic stellate cell activation and fibrosis
LPS 与 TLR4 结合调节肝星状细胞活化和纤维化
- 批准号:
8223187 - 财政年份:2011
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$ 33.25万 - 项目类别:
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