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

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

项目成果

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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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