Determining how chronic ETOH influences the regenerative activities of hepatocyte subpopulations

确定慢性 ETOH 如何影响肝细胞亚群的再生活动

基本信息

  • 批准号:
    10616522
  • 负责人:
  • 金额:
    $ 54.84万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-01 至 2026-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Alcoholic liver disease (ALD) is exacerbated by impaired liver regeneration. The cellular basis of liver regeneration is unclear and whether hepatocytes in different zones differ in regenerative activity is unclear, in part because fate-mapping has only been performed on a few hepatocyte subsets. The liver is organized into zones in which hepatocytes express different metabolic enzymes. To systematically compare the regenerative activities of these distinct subsets of hepatocytes, we developed twelve new CreER strains. Lineage tracing during normal homeostasis showed that cells from periportal zone 1 and pericentral zone 3 contracted in number, while cells from mid-lobular zone 2 expanded in number. Hepatocytes in different regions of the liver thus exhibit differences in turnover and zone 2 is an important source of new hepatocytes during homeostasis. Because zone 2 may represent a reserve population sheltered from pericentral and periportal liver injuries, we hypothesize that these cells also preferentially repopulate livers exposed to modest chronic injuries such as alcohol. Our preliminary scRNA-seq and in vivo CRISPR screens identified two critical zone 2 specific genes that regulate zone 2 hepatocyte proliferation and survival: Igfbp2 and Hamp2. Both of these secreted factors are suppressed in NAFLD and ALD in humans, which suggests functional importance in disease. Igfbp2 operates through mTOR and Ccnd1 to promote zone 2 hepatocyte proliferation. Hamp1 and Hamp2 encode for hepcidins, which negatively regulate iron uptake by inhibition of iron transporters and thus protects the body from iron overload. Patients with ALD accumulate hepatic iron through suppression of hepcidins. Free iron enhances reactive oxygen species (ROS) production in the liver, leading to alcohol-induced liver injury. We hypothesize that ALD pathogenesis is accelerated through the suppression of Igfbp2 and Hamp1/2, and that this involves changes in the number or function of zone 2 hepatocytes. In Aim 1, we will first use our CreER models to systematically determine the extent to which zone 2 cells repopulate the liver in the setting of ETOH. To understand how zone 2 cell might be involved in regeneration after ETOH, we will perturb two critical zone 2 genes using loss and gain of function approaches. In Aim 2, we will ask if Igfbp2 is necessary and sufficient to regulate the frequency or repopulating activities of zone 2 cells in the context of ETOH. In Aim 3, we will ask if Hamp1 and Hamp2 are necessary and sufficient to regulate the frequency or repopulating activities of zone 2 cells. Success in this project will for the first time define the cellular basis of regeneration in response to ETOH, allow us to focus on critical subpopulations, and determine the importance of two critical zone 2 specific genes in ALD.
项目总结

项目成果

期刊论文数量(0)
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Hao Zhu其他文献

Hao Zhu的其他文献

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{{ truncateString('Hao Zhu', 18)}}的其他基金

Mechanism-Driven Virtual Adverse Outcome Pathway Modeling for Hepatotoxicity
机制驱动的肝毒性虚拟不良结果途径建模
  • 批准号:
    10940417
  • 财政年份:
    2023
  • 资助金额:
    $ 54.84万
  • 项目类别:
Mechanism-Driven Virtual Adverse Outcome Pathway Modeling for Hepatotoxicity
机制驱动的肝毒性虚拟不良结果途径建模
  • 批准号:
    10675944
  • 财政年份:
    2023
  • 资助金额:
    $ 54.84万
  • 项目类别:
Virtual nanostructure simulation (VINAS) portal
虚拟纳米结构模拟 (VINAS) 门户
  • 批准号:
    10567076
  • 财政年份:
    2023
  • 资助金额:
    $ 54.84万
  • 项目类别:
Determining how chronic ETOH influences the regenerative activities of hepatocyte subpopulations
确定慢性 ETOH 如何影响肝细胞亚群的再生活动
  • 批准号:
    10297361
  • 财政年份:
    2021
  • 资助金额:
    $ 54.84万
  • 项目类别:
Determining how chronic ETOH influences the regenerative activities of hepatocyte subpopulations
确定慢性 ETOH 如何影响肝细胞亚群的再生活动
  • 批准号:
    10458730
  • 财政年份:
    2021
  • 资助金额:
    $ 54.84万
  • 项目类别:
Investigating imitation SWI chromatin remodeling complexes in mammalian tissue regeneration
研究哺乳动物组织再生中的仿 SWI 染色质重塑复合物
  • 批准号:
    10436812
  • 财政年份:
    2020
  • 资助金额:
    $ 54.84万
  • 项目类别:
Improving hepatocellular carcinoma mouse modeling by understanding the malignant potential and biology of liver cell subpopulations
通过了解肝细胞亚群的恶性潜能和生物学来改善肝细胞癌小鼠模型
  • 批准号:
    10610474
  • 财政年份:
    2020
  • 资助金额:
    $ 54.84万
  • 项目类别:
Mechanism-Driven Virtual Adverse Outcome Pathway Modeling for Hepatotoxicity
机制驱动的肝毒性虚拟不良结果途径建模
  • 批准号:
    10350701
  • 财政年份:
    2020
  • 资助金额:
    $ 54.84万
  • 项目类别:
Improving hepatocellular carcinoma mouse modeling by understanding the malignant potential and biology of liver cell subpopulations
通过了解肝细胞亚群的恶性潜能和生物学来改善肝细胞癌小鼠模型
  • 批准号:
    10172879
  • 财政年份:
    2020
  • 资助金额:
    $ 54.84万
  • 项目类别:
Mechanism-Driven Virtual Adverse Outcome Pathway Modeling for Hepatotoxicity
机制驱动的肝毒性虚拟不良结果途径建模
  • 批准号:
    10166848
  • 财政年份:
    2020
  • 资助金额:
    $ 54.84万
  • 项目类别:

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揭示视黄酸受体β在酒精性肝病中的作用
  • 批准号:
    10019450
  • 财政年份:
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Alcoholic Liver Diseases: Damage, Repair and Stem Cell Regeneration
酒精性肝病:损伤、修复和干细胞再生
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