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
基本信息
- 批准号:9753207
- 负责人:
- 金额:$ 39.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-02-15 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated Regions4-methylumbelliferoneBindingBinding SitesBiologicalBiological ProcessBloodBrainCD44 geneCause of DeathCholestasisCirrhosisCollagenComputer SimulationDataDepositionDevelopmentDiseaseDisease ProgressionEnzymesExtracellular MatrixFibronectinsFibrosisGenesGenetic TranscriptionGrantHAS2 geneHAS3 geneHeartHepatic Stellate CellHepatitis BHepatitis CHumanHyaluronanHyaluronic AcidHyaluronic Acid BindingHyaluronidaseIn VitroInfectionInflammationInjuryInterventionJointsKidneyKnock-outKnockout MiceLiverLiver CirrhosisLiver FibrosisLungMediatingMedicalMicroRNAsModelingMolecularMolecular WeightMusPathway interactionsPatientsPharmaceutical PreparationsPlayPost-Transcriptional RegulationProductionPromoter RegionsPublicationsPulmonary FibrosisReactive Oxygen SpeciesRoleSignal TransductionSourceTLR4 geneTestingTissue SampleTissuesToll-like receptorsToxinTranscriptional RegulationTransforming Growth Factor betaTransgenic OrganismsWT1 genebasechronic liver diseasecurative treatmentsgain of functionhuman tissuehyaluronan synthase 1in vivoinhibitor/antagonistliver developmentliver inflammationliver transplantationmigrationnonalcoholic steatohepatitisproblem drinkerprotective effectreceptortherapeutic evaluation
项目摘要
Project Summary
Liver fibrosis is the consequence of chronic liver diseases, such as hepatitis B and C infection, and
alcoholic and non-alcoholic steatohepatitis (NASH). Currently there is no effective anti-fibrotic agent for liver
cirrhosis. Therefore, the unmet medical needs for liver fibrosis/cirrhosis are significant.
Liver inflammation is a crucial mechanism for activation of hepatic stellate cell (HSCs) and liver fibrosis.
Activated HSCs produce extracellular matrix (ECM) including collagen, fibronectin, and hyaluronic acids (HA).
Endogenous HA have been implicated in the disease progression of lungs, kidneys, joints, heart, and brain. In
the liver, patients with liver cirrhosis show elevated HA levels in the blood. However, the biological functions of
endogenous HA produced in liver fibrosis have not been determined. HA are produced in high molecular
weight forms (HMW; MW>1000kDa) by hyaluronan synthase (HAS) 1-3. In the setting of inflammation, HA are
degraded into low molecular weight (LMW) forms (MW~100-300kDa). LMW-HA exacerbates tissue injury and
inflammation through binding to its receptors, CD44 and TLR4.
The objective of this study is to determine the biological functions of endogenous HA and its
downstream effector pathway in HSC activation and in liver fibrosis. Based on previous publications and
our preliminary studies, we hypothesize that HAS2-mediated HSC-derived HA and HA's downstream
effector pathways promote HSC activation and liver fibrosis. Moreover, we further hypothesize that by
targeting HA a new interventional strategy for treating liver fibrosis can be developed.
To test our hypotheses, we will investigate if HAS2-mediated HA production in HSCs promotes liver
fibrosis through loss- and gain-of-function approaches using HSC-specific Has2 knockout (Has2∆HSC) mice and
HAS2 transgenic (ASMA-HAS2 Tg) mice. We will also use human tissue samples to examine HSCs as the
source of HAS2 and HA in human cirrhotic livers (Aim 1). We will investigate the transcriptional and
posttranscriptional regulation of HAS2 expression in HSCs as the molecular mechanisms of dysregulated
HAS2 expression in liver fibrosis (Aim 2). We will then investigate the role of Notch1 signaling as the HA's
downstream effector pathway for HSC activation and liver fibrosis (Aim 3). Finally, we will examine
interventional potential of blocking HA synthesis for treating liver fibrosis (Aim 4).
项目总结
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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LPS binding to TLR4 regulates hepatic stellate cell activation and fibrosis
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LPS binding to TLR4 regulates hepatic stellate cell activation and fibrosis
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