Delineating the molecular mechanisms of hepatocyte-to-cholangiocyte reprogramming
描述肝细胞到胆管细胞重编程的分子机制
基本信息
- 批准号:10415302
- 负责人:
- 金额:$ 51.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:Bile fluidBiliaryCell modelCharacteristicsChemicalsCholestasisCirrhosisDataEP300 geneEpithelial CellsExhibitsFibrosisGene Expression RegulationGenesGeneticGenetic studyGoalsHDAC1 geneHepaticHepatocyteHistone AcetylationImageInjuryIntrahepatic bile ductLifeLiverLiver FailureLiver RegenerationLiver diseasesMS-275MediatingModelingMolecularMorbidity - disease rateMusNatural regenerationObstructionPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPharmacology StudyPhenocopyProcessReceptor GeneResearchRoleSignal TransductionStat3 proteinTestingTherapeuticZebrafishbasebeta cateninbiliary tractcholangiocyteeffective therapyend stage liver diseasegain of functioninhibitorinnovationinsightliver injuryliver transplantationmortalitymutantnotch proteinnovelsmall moleculetooltransdifferentiation
项目摘要
ABSTRACT
Biliary epithelial cells (BECs; also called as cholangiocytes) that line the hepatic biliary tree control bile
composition and flow. Injury to the BECs leads to cholestasis, which can progress to fibrosis, cirrhosis and liver
failure. Cholestatic liver diseases are associated with high morbidity and mortality; however, few effective
therapies are available. In fact, liver transplantation is the only life-extending treatment for end-stage cholestatic
liver diseases, but the shortage of donor livers makes this therapy extremely limited. In the injured liver with
biliary damage, hepatocytes (HCs) can contribute to BECs to recover from the loss of BECs. Recent studies in
mice have shown that HC-derived BECs contribute to the intrahepatic bile ducts, thereby restoring appropriate
bile flow. Patients with biliary obstruction or cholangiopathies also exhibit biliary marker expression in HCs,
suggesting their reprogramming into BECs. Thus, augmenting innate HC-to-BEC reprogramming in cholestatic
liver diseases is an attractive therapeutic alternative to ameliorate cholestasis and subsequent cirrhosis. To
develop such a therapy, it is crucial to better understand the molecular mechanisms underlying HC-to-BEC
reprogramming. Furthermore, identifying small molecules that can augment the reprogramming should provide
promising therapeutic drugs for patients with cholestatic liver diseases. Our long-term goal is to completely
delineate the molecular mechanisms underlying HC-to-BEC reprogramming. As a first step in pursuit of that goal,
the objective of this proposal is to determine the cellular and molecular characteristics of HC-to-BEC
reprogramming-driven biliary regeneration in our two innovative zebrafish models and to elucidate how histone
deacetylase 1 (hdac1) regulates HC-to-BEC reprogramming. Based on our preliminary data obtained from
pharmacological and genetic studies, we hypothesize that Hdac1 inhibition promotes HC-to-BEC reprogramming
by derepressing the Notch receptor gene notch2 and the signal transducer and activator of transcription 3 gene
(stat3). We will test this hypothesis and accomplish the objective of this application by (1) elucidating the entire
process of HC-to-BEC reprogramming-driven biliary regeneration in the two zebrafish models, in which complete
absence of BECs is achieved and subsequently HCs convert to BECs. (Aim 1), (2) determining the effects of
Hdac1 inhibition on HC-to-BEC reprogramming in both zebrafish and mice (Aim 2), and (3) elucidating the
molecular mechanisms by which Hdac1 inhibition promotes the reprogramming (Aim 3). The successful
accomplishment of the proposed research will not only provide novel molecular mechanisms underlying HC-to-
BEC reprogramming but also suggest HDAC1/2 inhibitors as promising therapeutic drugs to promote the
reprogramming in patients with cholestatic liver diseases.
摘要
胆管上皮细胞(BEC;也称为胆管细胞)排列在肝胆管树上,控制胆汁
组成和流动。BEC的损伤导致胆汁淤积,其可进展为纤维化、肝硬化和肝硬化。
失败胆汁淤积性肝病与高发病率和死亡率相关;然而,很少有有效的治疗方法。
治疗是可行的。事实上,肝移植是终末期胆汁淤积症唯一的延长生命的治疗方法
肝脏疾病,但供体肝脏的短缺使得这种治疗非常有限。在受伤的肝脏中,
在胆损伤中,肝细胞(HC)可有助于BEC从BEC的损失中恢复。的近期研究
小鼠已经表明,HC衍生的BEC有助于肝内胆管,从而恢复适当的
胆汁流量胆道梗阻或胆管病患者也表现出HC中的胆汁标志物表达,
表明它们被重新编程为BEC。因此,在胆汁淤积性疾病中增加先天性HC-至-BEC重编程,
肝病是改善胆汁淤积和随后的肝硬化的有吸引力的治疗选择。到
为了开发这种疗法,更好地理解HC到BEC的分子机制至关重要
重新编程此外,识别可以增强重编程的小分子应该提供
胆汁淤积性肝病患者的有前途的治疗药物。我们的长期目标是
描述HC到BEC重编程的分子机制。作为实现这一目标的第一步,
本计划的目的是确定HC-到-BEC的细胞和分子特征
在我们的两个创新的斑马鱼模型中重新编程驱动的胆汁再生,并阐明组蛋白如何
去乙酰化酶1(hdac 1)调节HC到BEC的重编程。根据我们从以下机构获得的初步数据,
通过药理学和遗传学研究,我们假设Hdac 1抑制促进HC到BEC的重编程
通过去抑制Notch受体基因notch 2和信号转导和转录激活因子3基因,
(stat3)。我们将测试该假设并通过以下方式实现本申请的目的:(1)阐明整个实施例,
在两种斑马鱼模型中,HC到BEC重编程驱动的胆汁再生过程,其中完全
实现了BEC的不存在,随后HC转化为BEC。(Aim(1)、(2)确定影响
Hdac 1对斑马鱼和小鼠中HC-至-BEC重编程的抑制(目的2),和(3)阐明Hdac 1对HC-至-BEC重编程的抑制作用。
Hdac 1抑制促进重编程的分子机制(Aim 3)。成功
这项研究的完成不仅将提供HC-到--
BEC重编程,但也表明HDAC 1/2抑制剂作为有前途的治疗药物,以促进
胆汁淤积性肝病患者的重编程。
项目成果
期刊论文数量(0)
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Donghun Shin其他文献
Donghun Shin的其他文献
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{{ truncateString('Donghun Shin', 18)}}的其他基金
Delineating the molecular mechanisms of hepatocyte-to-cholangiocyte reprogramming
描述肝细胞到胆管细胞重编程的分子机制
- 批准号:
10596146 - 财政年份:2022
- 资助金额:
$ 51.49万 - 项目类别:
Elucidating the Mechanisms by which Bmp Signaling Regulates Biliary-Driven Liver Regeneration
阐明 Bmp 信号调节胆道驱动的肝脏再生的机制
- 批准号:
9270021 - 财政年份:2014
- 资助金额:
$ 51.49万 - 项目类别:
Elucidating the Mechanisms by which Bmp Signaling Regulates Biliary-Driven Liver Regeneration
阐明 Bmp 信号调节胆道驱动的肝脏再生的机制
- 批准号:
8813644 - 财政年份:2014
- 资助金额:
$ 51.49万 - 项目类别:
Elucidating the role of the FXR-PTEN-PI3K-AKT-mTOR axis in liver progenitor cell-driven liver regeneration
阐明 FXR-PTEN-PI3K-AKT-mTOR 轴在肝祖细胞驱动的肝再生中的作用
- 批准号:
10402799 - 财政年份:2014
- 资助金额:
$ 51.49万 - 项目类别:
Elucidating the role of the FXR-PTEN-PI3K-AKT-mTOR axis in liver progenitor cell-driven liver regeneration
阐明 FXR-PTEN-PI3K-AKT-mTOR 轴在肝祖细胞驱动的肝再生中的作用
- 批准号:
10620261 - 财政年份:2014
- 资助金额:
$ 51.49万 - 项目类别:
Elucidating the Mechanisms by which Bmp Signaling Regulates Biliary-Driven Liver Regeneration
阐明 Bmp 信号调节胆道驱动的肝脏再生的机制
- 批准号:
8931956 - 财政年份:2014
- 资助金额:
$ 51.49万 - 项目类别:
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