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).
项目摘要
肝纤维化是慢性肝病的结果,如B肝炎和丙型肝炎感染,
酒精性和非酒精性脂肪性肝炎(NASH)。目前尚无有效的抗肝纤维化药物
肝硬化因此,肝纤维化/肝硬化的未满足的医疗需求是显著的。
肝脏炎症是肝星状细胞(hepatic stellate cell,HSCs)活化和肝纤维化的重要机制。
活化的HSC产生细胞外基质(ECM),包括胶原蛋白、纤连蛋白和透明质酸(HA)。
内源性HA与肺、肾、关节、心脏和脑的疾病进展有关。在
肝硬化患者血液中HA水平升高。然而,
肝纤维化中产生的内源性HA尚未确定。HA是以高分子
由透明质酸合酶(HAS)1-3形成的重量形式(HMW; MW> 1000 kDa)。在炎症环境中,HA
降解为低分子量(LMW)形式(MW约100- 300 kDa)。LMW-HA加剧组织损伤,
炎症通过结合其受体CD 44和TLR 4。
本研究的目的是确定内源性HA的生物学功能及其在肿瘤发生发展中的作用。
在HSC活化和肝纤维化中的下游效应子途径。根据以前的出版物和
在我们的初步研究中,我们假设HAS 2介导的HSC衍生的HA和HA的下游
效应子途径促进HSC活化和肝纤维化。此外,我们进一步假设,
以HA为靶点,可以开发一种治疗肝纤维化的新的干预策略。
为了验证我们的假设,我们将研究HSC中HAS 2介导的HA产生是否促进肝脏
使用HSC特异性Has 2敲除(Has 2 β HSC)小鼠通过功能丧失和获得方法治疗纤维化,
HAS 2转基因(ASMA-HAS 2 Tg)小鼠。我们还将使用人体组织样本来检查HSC,
人肝病中HAS 2和HA的来源(目的1)。我们将研究转录和
HSC中HAS 2表达的转录后调控是调控失调的分子机制
HAS 2在肝纤维化中的表达(目的2)。然后,我们将研究Notch 1信号传导作为HA的作用。
HSC活化和肝纤维化的下游效应子途径(Aim 3)。最后,我们将研究
阻断HA合成治疗肝纤维化的干预潜力(目的4)。
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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EKIHIRO SEKI其他文献
EKIHIRO SEKI的其他文献
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LPS binding to TLR4 regulates hepatic stellate cell activation and fibrosis
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