Regulation of HNF4 in Hepatic Failure in Cirrhosis
HNF4 在肝硬化肝衰竭中的调控
基本信息
- 批准号:8560395
- 负责人:
- 金额:$ 59.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-15 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAlcoholsAnimalsCCL4 geneCell AgingCellsCessation of lifeChIP-seqCharacteristicsChildChromatinChronicCirrhosisCirrhotic hepatocyteDefectDown-RegulationETS1 geneEZH2 geneEtiologyExhibitsFailureFunctional disorderGene ExpressionGene Expression ProfileGenesHepaticHepatitis B VirusHepatitis C virusHepatocyteHumanIL6 geneImmuneInfectionInjuryLeadLiverLiver CirrhosisLiver FailureLiver RegenerationLiver diseasesMADH4 geneMental DepressionMetabolicModelingMusNR4A1 geneNatural regenerationNuclear ReceptorsPatientsPhenotypePublic HealthRattusRecombinantsRegulationRepressionRodentSeriesSignal PathwaySignal Transduction PathwayStagingTNF geneTNFRSF5 geneTelomeraseTelomere ShorteningTimeTranscriptional ActivationTransplantationUnited StatesVirusadeno-associated viral vectorchronic liver diseaseclinical efficacygenome-widehuman HNF4A proteinimprovedimproved functioningliver functionliver injuryloss of functionp65promoterpublic health relevancerepairedrestorationtranscription factortranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): The cause of liver failure in cirrhosis is not well understood, as the liver is capable of regeneration and functions normally despite loss of more than half of its hepatocytes. Hepatic failure in cirrhosis therefore results from additional dysfunction of the remaining hepatocytes. Our Preliminary Studies showed that primary hepatocytes derived from cirrhotic livers with decompensated function exhibit numerous alterations in gene expression and proliferative capacity. Yet, despite critical shortening of telomeres and loss of telomerase activity, these hepatocytes can eventually recover their capacity for regeneration and function after transfer into a normal liver. Our transcriptome analysis demonstrated that progression to hepatocyte failure was associated with down regulation of transcription factor HNF4¿ and suppression of its regulatory network. Since HNF4¿ deficiency could explain the depression of downstream effectors, mature hepatocyte-specific genes, and general hepatic function, we studied end-stage cirrhotic hepatocytes in culture and found that HNF4¿ expression, restored via AAV transduction, dramatically and immediately corrected the phenotype. Next, AAV-HNF4¿ was given IV to rodents with decompensated cirrhosis. Their hepatocyte function improved to almost normal levels within 2 weeks and survival was prolonged from ~2 weeks to more than 100 days! Thus, disruption of HNF4¿ transcriptional activation appears to be the mechanism responsible for hepatic failure in advanced cirrhosis. We therefore hypothesize that restoration of HNF4¿ will effectively treat cirrhotic patients with end-stage liver failure by correcting the metabolic defects and reversing the hepatocyte replicative senescence. In these studies we will use a recombinant AAV vector that encodes HNF4¿ driven from an inducible promoter to determine whether short term treatment with HNF4¿ can lead to sustained normalization of hepatic function and survival. In addition, we will assess the utility of HNF4¿-AAV treatment during continuing injury with CCL4 to determine the potential clinical efficacy of such therapy. To determine the mechanism of HNF4¿ downregulation in decompensated cirrhosis, we will perform a genome-wide ChIP-Seq analysis of isolated hepatocytes and whole liver. Finally, we will determine the extent to which human end-stage cirrhotic livers share the same characteristics as those identified in our rodent studies, and will determine the extent that restoration of HNF4¿ expression can normalize human hepatocytes derived from these end-stage livers.
描述(申请人提供):肝功能衰竭的原因不是很清楚,因为肝脏能够再生和功能正常,尽管其一半以上的肝细胞损失。因此,肝硬变中的肝功能衰竭是由于剩余肝细胞的额外功能障碍所致。我们的初步研究表明,功能失代偿的肝硬变来源的原代肝细胞在基因表达和增殖能力方面出现了许多变化。然而,尽管端粒严重缩短和端粒酶活性丧失,这些肝细胞在移植到正常肝脏后最终可以恢复其再生和功能的能力。我们的转录组分析表明,进展为肝细胞衰竭与转录因子HNF4的下调及其调控网络的抑制有关。由于HNF4缺乏可以解释下游效应、成熟的肝细胞特异性基因和一般肝功能的抑制,我们研究了培养的终末期肝硬变肝细胞,发现通过AAV转导恢复的HNF4表达显著并立即纠正了表型。接下来,给失代偿期肝硬变大鼠静脉注射AAV-HNF4。肝细胞功能在2周内恢复到接近正常的水平,存活时间从~2周延长到100天以上!因此,HNF4转录激活的中断似乎是晚期肝硬变患者肝功能衰竭的机制。因此,我们假设HNF4的恢复将通过纠正代谢缺陷和逆转肝细胞的复制衰老而有效地治疗伴有终末期肝功能衰竭的肝硬变患者。在这些研究中,我们将使用编码由可诱导启动子驱动的HNF4的重组AAV载体来确定HNF4短期治疗是否可以导致肝功能和存活率的持续正常化。此外,我们将评估HNF4?-AAV在持续损伤期间用CCl4治疗的有效性,以确定这种治疗的潜在临床疗效。为了确定失代偿性肝硬变中HNF4下调的机制,我们将对分离的肝细胞和整个肝脏进行全基因组芯片序列分析。最后,我们将确定人类终末期肝硬变在多大程度上与我们的啮齿动物研究中发现的特征相同,并将确定恢复HNF4表达的程度可以使来自这些终末期肝脏的人类肝细胞正常化。
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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Ira J. Fox其他文献
Clonal deletion: a mechanism of tolerance in mixed bone marrow chimeras.
克隆缺失:混合骨髓嵌合体的耐受机制。
- DOI:
- 发表时间:
1990 - 期刊:
- 影响因子:2.2
- 作者:
Jack C. Yu;Marianne Webster;Ira J. Fox - 通讯作者:
Ira J. Fox
A new technique for combined liver/small intestinal transplantation.
肝/小肠联合移植新技术。
- DOI:
10.1097/00007890-200112150-00025 - 发表时间:
2001 - 期刊:
- 影响因子:6.2
- 作者:
D. Sudan;Kishore Iyer;Arnaud DeRoover;S. Chinnakotla;Ira J. Fox;B. Shaw;A. Langnas - 通讯作者:
A. Langnas
Human hepatocyte transplantation: gene therapy and more?
人肝细胞移植:基因疗法等等?
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:8
- 作者:
J. Chowdhury;N. Chowdhury;Stephen C. Strom;Stuart S. Kaufman;Simon Horslen;Ira J. Fox - 通讯作者:
Ira J. Fox
Ira J. Fox的其他文献
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{{ truncateString('Ira J. Fox', 18)}}的其他基金
Hepatocyte Transplantation for Liver Based Metabolic Disease
肝细胞移植治疗肝脏代谢疾病
- 批准号:
9762098 - 财政年份:2018
- 资助金额:
$ 59.51万 - 项目类别:
Hepatocyte xenografts for treatment of acute liver failure
肝细胞异种移植治疗急性肝衰竭
- 批准号:
9128195 - 财政年份:2016
- 资助金额:
$ 59.51万 - 项目类别:
Hepatocyte xenografts for treatment of acute liver failure
肝细胞异种移植治疗急性肝衰竭
- 批准号:
9236158 - 财政年份:2016
- 资助金额:
$ 59.51万 - 项目类别:
Regulation of HNF4 in Hepatic Failure in Cirrhosis
HNF4 在肝硬化肝衰竭中的调控
- 批准号:
9084549 - 财政年份:2013
- 资助金额:
$ 59.51万 - 项目类别:
Regulation of HNF4 in Hepatic Failure in Cirrhosis
HNF4 在肝硬化肝衰竭中的调控
- 批准号:
8892178 - 财政年份:2013
- 资助金额:
$ 59.51万 - 项目类别:
Regulation of HNF4 in Hepatic Failure in Cirrhosis
HNF4 在肝硬化肝衰竭中的调控
- 批准号:
8698412 - 财政年份:2013
- 资助金额:
$ 59.51万 - 项目类别:
Models of AT Deficiency Using Human Hepatocytes
使用人肝细胞的 AT 缺陷模型
- 批准号:
10630350 - 财政年份:2012
- 资助金额:
$ 59.51万 - 项目类别:
Models of AT Deficiency Using Human Hepatocytes
使用人肝细胞的 AT 缺陷模型
- 批准号:
10197889 - 财政年份:2012
- 资助金额:
$ 59.51万 - 项目类别:
Models of AT Deficiency Using Human Hepatocytes
使用人肝细胞的 AT 缺陷模型
- 批准号:
10441251 - 财政年份:2012
- 资助金额:
$ 59.51万 - 项目类别:
Xenogeneic Hepatocyte Transplantation for Cirrhosis
异种肝细胞移植治疗肝硬化
- 批准号:
6686109 - 财政年份:2003
- 资助金额:
$ 59.51万 - 项目类别:
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