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:10458730
- 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
- 来源:
- 关键词:Alcoholic Liver DiseasesAlcoholsCRISPR screenCell ProliferationCell physiologyCellsChronicContractsDataDiseaseEnzymesEthanolExhibitsExposure toFRAP1 geneFrequenciesGenesGenetic TranscriptionHepaticHepatocyteHomeostasisHumanImpairmentInjuryIronIron OverloadIron Uptake InhibitionLabelLiverLiver RegenerationLobularMetabolicModelingMorbidity - disease rateNatural regenerationPathogenesisPatientsPopulationProductionProliferatingReactive Oxygen SpeciesRegulationSourceTimeTissuesgain of functionhealinghepcidinin vivoliver cell proliferationliver injurymortalitynon-alcoholic fatty liver diseaseoverexpressionregenerativeresponsesingle-cell RNA sequencingsuccesstissue repair
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)
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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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
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机制驱动的肝毒性虚拟不良结果途径建模
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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
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Virtual nanostructure simulation (VINAS) portal
虚拟纳米结构模拟 (VINAS) 门户
- 批准号:
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$ 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
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- 批准号:
10610474 - 财政年份:2020
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Mechanism-Driven Virtual Adverse Outcome Pathway Modeling for Hepatotoxicity
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Improving hepatocellular carcinoma mouse modeling by understanding the malignant potential and biology of liver cell subpopulations
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$ 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
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10166848 - 财政年份:2020
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