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

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):肝硬化肝衰竭的原因尚不清楚,因为尽管损失了一半以上的肝细胞,肝脏仍能够再生并正常发挥功能。因此,肝硬化中的肝衰竭是由剩余肝细胞的额外功能障碍引起的。我们的初步研究表明,源自功能失代偿的肝硬化肝脏的原代肝细胞在基因表达和增殖能力方面表现出许多改变。然而,尽管端粒严重缩短并且端粒酶活性丧失,这些肝细胞在转移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,肝细胞衰竭的进展与转录因子 HNF4 的下调及其调控网络的抑制有关。由于 HNF4¿ 缺陷可以解释下游效应器、成熟肝细胞特异性基因和一般肝功能的抑制,因此我们研究了培养的终末期肝硬化肝细胞,发现通过 AAV 转导恢复的 HNF4 表达,显着且立即纠正了表型。接下来,对失代偿性肝硬化啮齿类动物进行静脉注射 AAV-HNF4。他们的肝细胞功能在 2 周内改善到几乎正常水平,生存期从约 2 周延长至 100 多天!因此,HNF4 转录激活的破坏似乎是晚期肝硬化肝衰竭的机制。因此,我们假设恢复HNF4将通过纠正代谢缺陷和逆转肝细胞复制衰老来有效治疗患有终末期肝衰竭的肝硬化患者。在这些研究中,我们将使用编码由诱导型启动子驱动的 HNF4 的重组 AAV 载体,以确定 HNF4 的短期治疗是否可以导致肝功能和存活的持续正常化。此外,我们将评估 HNF4-AAV 治疗在 CCL4 持续损伤期间的效用,以确定此类治疗的潜在临床疗效。为了确定失代偿性肝硬化中 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 ChIP-Seq 分析。最后,我们将确定人类终末期肝硬化肝脏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 HNF4 表达的恢复可以在多大程度上使源自这些终末期肝脏的人类肝细胞正常化。

项目成果

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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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