Role of Early Growth Response Factor-1 in Cholestatic Liver Injury

早期生长反应因子 1 在胆汁淤积性肝损伤中的作用

基本信息

  • 批准号:
    7484469
  • 负责人:
  • 金额:
    $ 8.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-05-01 至 2012-04-30
  • 项目状态:
    已结题

项目摘要

The overall goal of this proposal is to elucidate the mechanism by which cholestasis triggers production of proinflammatory mediators in the liver. Cholestatic liver disease arises when excretion of bile acids from the liver is interrupted. This results in the accumulation of bile acids in the liver, hepatic inflammation, and hepatocyte injury. The pathogenesis of hepatocyte injury during cholestasis depends in part on the release of proinflammatory mediators that cause neutrophils to accumulate in the liver and become activated to damage hepatocytes. Interestingly, inflammation associated with cholestasis occurs independently of tumor necrosis factor-a or interteukin-1, suggesting that this process is regulated by a novel, previously undescribed mechanism. Our preliminary studies indicate that the transcription factor, early growth response factor-1 (Egr-1), is critical for this process. Egr-1 is rapidly upregulated in hepatocytes during cholestasis. Upregulation of Egr-1 appears to be mediated directly by bile acids, since exposure of primary mouse hepatocytes to pathological concentrations of bile acids upregulates Egr-1. Our studies show further that upregulation of macrophage inflammatory protein-2, intercellular adhesion molecule-1, neutrophil accumulation, and hepatocyte injury are dramatically reduced in Egr-1 knockout mice with cholestasis. These preliminary results suggest that upregulation of Egr-1 in hepatocytes is vital for the development of neutrophil-dependent inflammatory liver injury. Furthermore, these studies indicate that Egr-1 provides the critical link between elevated concentrations of bile acids and the production of proinflammatory mediators in liver. Therefore, the main hypothesis of this proposal is that during early stages of cholestasis, elevated concentrations of bile acids upregulate Egr-1 in hepatocytes, which increases expression of proinflammatory mediators that cause neutrophils to accumulate in the liver and become activated to damage hepatocytes. The studies in this proposal aim to test this hypothesis by: (1) elucidating the molecular mechanism(s) by which bile acids upregulate Egr-1 in hepatocytes, (2) determining whether Egr-1 regulates proinflammatory mediator expression by hepatocytes, and (3) determining whether bile acids increase proinflammatory mediator expression by hepatocytes through Egr-1-dependent mechanisms. A greater understanding of the molecular mechanism(s) by which Egr-1 mediates hepatocellular injury during cholestasis could provide insight into ways to treat this disease in humans. Furthermore, since bile acid concentrations are increased in several types of liver disease in humans, this pathway could also prove to be an important, general mechanism of inflammatory injury in the liver.
该提案的总体目标是阐明胆汁淤积触发产生 肝脏中的促炎介质。胆汁淤积性肝病是由于胆汁酸从肝内排出, 肝脏被打断了。这导致胆汁酸在肝脏中的积累,肝脏炎症, 肝细胞损伤胆汁淤积时肝细胞损伤的发病机制部分取决于 导致中性粒细胞在肝脏中积聚并被激活, 损害肝细胞。有趣的是,与胆汁淤积相关的炎症与肿瘤无关, 坏死因子-a或白细胞介素-1,表明这一过程是由一种新的,以前 未描述的机制。我们的初步研究表明,转录因子,早期生长, 响应因子-1(Egr-1)对该过程至关重要。Egr-1在肝细胞中快速上调, 胆汁淤积Egr-1的上调似乎是由胆汁酸直接介导的,因为暴露于原发性胆汁酸, 小鼠肝细胞到病理浓度的胆汁酸上调Egr-1。我们的研究进一步表明, 巨噬细胞炎性蛋白-2、细胞间粘附分子-1、中性粒细胞 在具有胆汁淤积的Egr-1敲除小鼠中,Egr-1的蓄积和肝细胞损伤显著降低。 这些初步结果表明,肝细胞中Egr-1的上调对肝细胞癌的发生至关重要。 嗜中性粒细胞依赖性炎性肝损伤。此外,这些研究表明,Egr-1提供了 胆汁酸浓度升高与促炎介质产生之间的关键联系 肝脏因此,该建议的主要假设是,在胆汁淤积的早期阶段, 胆汁酸浓度上调肝细胞中的Egr-1,这增加了促炎因子的表达。 介体,其导致中性粒细胞在肝脏中积聚并被激活以损伤肝细胞。 本提案中的研究旨在通过以下方式验证这一假设:(1)阐明分子机制, 其中胆汁酸上调肝细胞中的Egr-1,(2)确定Egr-1是否调节促炎性 通过肝细胞的介体表达,和(3)确定胆汁酸是否增加促炎性因子表达, 通过Egr-1依赖性机制介导肝细胞表达。更好地了解 Egr-1介导胆汁淤积期间肝细胞损伤的分子机制可以提供 深入了解人类治疗这种疾病的方法。此外,由于胆汁酸浓度增加, 在人类的几种类型的肝病中,这一途径也可能被证明是一种重要的,普遍的, 肝脏炎症损伤的机制。

项目成果

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Bryan L Copple其他文献

Bryan L Copple的其他文献

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{{ truncateString('Bryan L Copple', 18)}}的其他基金

Novel proteolytic mechanisms driving pathologic hepatic congestion in drug-induced hepatotoxicity
药物引起的肝毒性中驱动病理性肝充血的新蛋白水解机制
  • 批准号:
    10638320
  • 财政年份:
    2023
  • 资助金额:
    $ 8.23万
  • 项目类别:
Macrophage Phenotypic Modulators—A Novel Therapeutic Approach to Liver Fibrosis Treatment
巨噬细胞表型调节剂——肝纤维化治疗的新方法
  • 批准号:
    10171770
  • 财政年份:
    2020
  • 资助金额:
    $ 8.23万
  • 项目类别:
COBRE: U OF KANSAS MEDICAL CTR: HISTOLOGY/PHENOTYPING CORE
COBRE:堪萨斯大学医学 CTR:组织学/表型核心
  • 批准号:
    8360782
  • 财政年份:
    2011
  • 资助金额:
    $ 8.23万
  • 项目类别:
COBRE: U OF KANSAS MEDICAL CTR: HISTOLOGY/PHENOTYPING CORE
COBRE:堪萨斯大学医学 CTR:组织学/表型核心
  • 批准号:
    8167661
  • 财政年份:
    2010
  • 资助金额:
    $ 8.23万
  • 项目类别:
COBRE: U OF KANSAS MEDICAL CTR: CORE D: HISTOLOGY/PHENOTYPING CORE
COBRE:堪萨斯大学医学 CTR:核心 D:组织学/表型核心
  • 批准号:
    7959505
  • 财政年份:
    2009
  • 资助金额:
    $ 8.23万
  • 项目类别:
COBRE: U OF KANSAS MEDICAL CTR: CORE D: HISTOLOGY/PHENOTYPING CORE
COBRE:堪萨斯大学医学 CTR:核心 D:组织学/表型核心
  • 批准号:
    7720182
  • 财政年份:
    2008
  • 资助金额:
    $ 8.23万
  • 项目类别:
Role of Early Growth Response Factor-1 in Cholestatic Liver Injury
早期生长反应因子 1 在胆汁淤积性肝损伤中的作用
  • 批准号:
    8371762
  • 财政年份:
    2007
  • 资助金额:
    $ 8.23万
  • 项目类别:
Role of Early Growth Response Factor-1 in Cholestatic Liver Injury
早期生长反应因子 1 在胆汁淤积性肝损伤中的作用
  • 批准号:
    7387478
  • 财政年份:
    2007
  • 资助金额:
    $ 8.23万
  • 项目类别:
Role of Early Growth Response Factor-1 in Cholestatic Liver Injury
早期生长反应因子 1 在胆汁淤积性肝损伤中的作用
  • 批准号:
    7259929
  • 财政年份:
    2007
  • 资助金额:
    $ 8.23万
  • 项目类别:
PROJ 4: PHYSIOLOGICAL FUNCTION OF NUCLEAR RECEPTORS IN CHOLESTATIC LIVER DISEASE
项目 4:核受体在胆汁淤积性肝病中的生理功能
  • 批准号:
    7610775
  • 财政年份:
    2007
  • 资助金额:
    $ 8.23万
  • 项目类别:

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