Inactivation of Hepatic Stellate Cells During Reversal of Liver Fibrosis
肝纤维化逆转过程中肝星状细胞失活
基本信息
- 批准号:9271180
- 负责人:
- 金额:$ 33.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-05-15 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAdultAffectBinding SitesBiochemicalBiologyCell modelCellsChIP-seqChronicCirrhosisCollagenCollagen Type IDNA BindingDataDepositionDetectionDevelopmentEpigenetic ProcessEventExtracellular Matrix ProteinsFlow CytometryGene ActivationGene ChipsGene ExpressionGene Expression ProfileGene TargetingGenesGenetic TranscriptionGoalsHealthcareHepatic Stellate CellHepatotoxicityHumanHuman GenomeIn VitroInjury to LiverInvestigationKnockout MiceLabelLinkLiverLiver FibrosisLiver diseasesLocationLoxP-flanked alleleMaintenanceMediatingMessenger RNAMolecularMusMyofibroblastPPAR gammaPathway interactionsPatientsPhenotypePopulationProductionRecoveryRegulationRegulator GenesRepressionReverse Transcriptase Polymerase Chain ReactionRoleSignal TransductionSiteSmall Interfering RNASourceStimulusSystemTIMP1 geneTamoxifenTestingTimeTranslatingTransplantationUp-Regulationbaseblocking factorcare burdengenome wide methylationgenome-widehistone modificationin vitro testingin vivoinjuredinsightinterestintrahepaticknock-downliver injurymRNA Expressionmouse genomemouse modelnoveloverexpressionpreventpublic health relevancepupresponsetherapeutic targettranscription factortranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): Chronic liver injury results in hepatic fibrosis, in which quiescent hepatic stellate cells (qHSCs) activate into myofibroblasts, depositing extensive extracellular matrix (ECM) proteins. Cessation of fibrogenic stimuli often results in regression of
liver fibrosis and is associated with the disappearance of activated HSCs (aHSCs)/myofibroblasts. We have recently demonstrated that some aHSCs apoptose, while other aHSCs inactivate (iHSCs) into a quiescent-like phenotype. The overall goals of this Project are to identify the molecular factors that may prevent HSC activation into myofibroblasts, or that revert aHSC into an inactivated state. Our central hypothesis is that genome wide epigenetic changes regulate HSC phenotype by activation (or suppression) of transcriptional activity in HSCs. We also hypothesize that activation of PPARγ-target genes regulates quiescent and inactivated HSC phenotypes. AIM1: We will assess the genome wide methylation and acetylation sites using ChIP-Seq in qHSCs, aHSCs and iHSCs in order to identify motifs and transcription factors critical for HSC inactivation. Using in vitro systems, we will determine f siRNA knock-down or overexpression of these factors blocks HSC activation, or triggers HSC inactivation. AIM2: We have demonstrated that PPARγ is re-expressed in HSCs during inactivation. To gain a greater insight into the mechanisms of HSC inactivation, we will conduct a broad investigation of the epigenetic changes that regulate PPARγ-target genes in distinct HSC phenotypes (qHSCs, aHSCs and iHSCs). We will test if functional inhibition of these genes affects the qHSC and iHSC phenotypes. AIM3: We will assess the role of PPARγ and PPARγ target genes in HSC biology in vivo using knockout mice, in which PPARγ is constitutively or inducibly deleted specifically in HSCs. A specific role of PPARγ in the maintenance of quiescent HSC phenotype and inactivation of aHSCs will be assessed in PPARγ-deficient HSCs versus wild type HSCs. We anticipate that the collective results obtained in AIMs 1-3 will identify specific factors that can revert aHSCs into an inactivated quiescent-like state. AIM4: Our
findings in mice must be translated to patients with fibrotic liver disease. To examine how human HSCs inactivate, quiescent human HSCs will be engrafted into livers of Rag2-/-γc-/- mice, and their activation will be induced in vivo by CCl4 followed by recovery. Human qHSCs, aHSCs and iHSCs will be isolated at each time point and analyzed by RT-PCR, Human genome microarray and flow cytometry. Next, human iHSCs will be subjected to ChIP-Seq analysis, and inactivation-specific targets will be identified (and compared to that in mouse iHSCs). The ability
of these targets to inactivate human aHSCs into a quiescent-like state will be tested in vitro and in vivo using siRNA knock-down or intrahepatic transplantation of human HSCs into Rag2-/-γc-/- mice. The results of our studies will give new insight into mechanisms underlying HSC inactivation in mice and patients, identifying potential therapeutic targets that can induce inactivation of activated HSCs/myofibroblasts in fibrotic liver.
描述(由申请人提供):慢性肝损伤导致肝纤维化,其中静止的肝星状细胞(qhsc)激活成肌成纤维细胞,沉积大量细胞外基质(ECM)蛋白。停止纤维原性刺激通常会导致退化
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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Tatiana Kisseleva其他文献
Tatiana Kisseleva的其他文献
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{{ truncateString('Tatiana Kisseleva', 18)}}的其他基金
The role of IL-17 signaling in alcohol-induced HCC
IL-17 信号在酒精诱导的 HCC 中的作用
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10299157 - 财政年份:2021
- 资助金额:
$ 33.71万 - 项目类别:
The role of IL-17 signaling in alcohol-induced HCC
IL-17 信号在酒精诱导的 HCC 中的作用
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10463697 - 财政年份:2021
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$ 33.71万 - 项目类别:
Novel IL-23 inhibitor for the treatment of alcohol associated liver disease
用于治疗酒精相关性肝病的新型 IL-23 抑制剂
- 批准号:
10482350 - 财政年份:2020
- 资助金额:
$ 33.71万 - 项目类别:
Novel IL-23 inhibitor for the treatment of alcohol associated liver disease
用于治疗酒精相关性肝病的新型 IL-23 抑制剂
- 批准号:
10266186 - 财政年份:2020
- 资助金额:
$ 33.71万 - 项目类别:
The Role of Portal Fibroblasts in Cholestatic Liver Fibrosis
门静脉成纤维细胞在胆汁淤积性肝纤维化中的作用
- 批准号:
10441586 - 财政年份:2014
- 资助金额:
$ 33.71万 - 项目类别:
Inactivation of Hepatic Stellate Cells During Reversal of Liver Fibrosis
肝纤维化逆转过程中肝星状细胞失活
- 批准号:
8694267 - 财政年份:2014
- 资助金额:
$ 33.71万 - 项目类别:
The Role of Portal Fibroblasts in Cholestatic Liver Fibrosis
门静脉成纤维细胞在胆汁淤积性肝纤维化中的作用
- 批准号:
10312314 - 财政年份:2014
- 资助金额:
$ 33.71万 - 项目类别:
Epigenetics of human Hepatic Stellate Cells (HSCs) in NASH
NASH 中人肝星状细胞 (HSC) 的表观遗传学
- 批准号:
10367096 - 财政年份:2014
- 资助金额:
$ 33.71万 - 项目类别:
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