Mechanisms of Hepatocyte Polarization and Apical Tube Formation

肝细胞极化和心尖管形成的机制

基本信息

  • 批准号:
    10391530
  • 负责人:
  • 金额:
    $ 38.41万
  • 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:
    2021-07-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract: The functions of the liver, including detoxification, synthesis of serum proteins, and bile production, critically depend on hepatocyte polarization and bile canaliculus (BC) formation. Defects in these processes are associated with serious liver diseases such as cholestasis and hepatocarcinoma. Using the rat hepatocyte line Can 10, the only known cells that can proliferate and form “tubular” BCs (tBCs) in vitro that resembles those in vivo, we discovered that hepatocyte polarization and “primordial” BC formation are linked to cytokinesis. This division-linked mechanism also applies to BC biogenesis during liver development. However, it remains a mystery how a primordial BC formed between two daughter cells at the division site is remodeled and grown into a tBC nestled between two rows of cells, as seen in the liver. We hypothesize that tBC formation involves spatiotemporal coordination of oriented divisions, with BC expansion driven by targeted exocytosis, elongation by pushing forces from both sides of the BC, and extension along the cell-cell contact through constant remodeling of the adherens and tight junctions. To identify the steps and key players involved, we employed two non-biased approaches. The first involves identification of genes from single-cell transcriptomic analysis of liver development that are induced or increased at stages of hepatocyte polarization and BC formation. The second involves identification of genes whose expressions are increased in the polarized Can 10 cells versus the unpolarized parental cells. These complementary approaches have led to the discovery of numerous genes that may play an important role in a process from the terminal stage of cytokinesis to tBC formation. 11 candidate genes were selected for a small siRNA-based screen, three (KIF21B, ABLIM3, and IPCEF1) were found to be required for tBC formation. None of these has been implicated previously in epithelial tube formation. In this application, we will use an interdisciplinary approach to test our hypotheses that the microtubule (MT) plus end-directed motor Kif21B and the actin-binding protein Ablim3 act in concert to drive BC expansion by controlling MT- and actin-mediated vesicle transport as well as adherens junction (AJ) assembly (Aim 1), and that the scaffold protein Ipcef1 promotes Arf6 activation by distinct cytohesins (GEFs) at distinct locations to control AJ remodeling, apical vesicle recycling, and actin-based protrusions to drive BC elongation (Aim 2). As the mechanisms of apical tube formation are highly conserved from worms to humans, the impact of our proposed study will likely reach far beyond the field of liver biology.
项目总结/文摘:

项目成果

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Erfei Bi其他文献

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{{ truncateString('Erfei Bi', 18)}}的其他基金

Mechanisms of Hepatocyte Polarization and Apical Tube Formation
肝细胞极化和心尖管形成的机制
  • 批准号:
    10221385
  • 财政年份:
    2021
  • 资助金额:
    $ 38.41万
  • 项目类别:
Mechanisms of Hepatocyte Polarization and Apical Tube Formation
肝细胞极化和心尖管形成的机制
  • 批准号:
    10598034
  • 财政年份:
    2021
  • 资助金额:
    $ 38.41万
  • 项目类别:
Analysis of Septin Structure and Function
Septin结构与功能分析
  • 批准号:
    10532365
  • 财政年份:
    2016
  • 资助金额:
    $ 38.41万
  • 项目类别:
Analysis of Septin Structure and Function
Septin结构与功能分析
  • 批准号:
    10316259
  • 财政年份:
    2016
  • 资助金额:
    $ 38.41万
  • 项目类别:
Analysis of Septin Structure and Function
Septin结构与功能分析
  • 批准号:
    10798852
  • 财政年份:
    2016
  • 资助金额:
    $ 38.41万
  • 项目类别:
Mechanistic Analysis of Cytokinesis in Eukaryotes
真核生物细胞分裂的机制分析
  • 批准号:
    9316658
  • 财政年份:
    2015
  • 资助金额:
    $ 38.41万
  • 项目类别:
Mechanistic Analysis of Cytokinesis in Eukaryotes
真核生物细胞分裂的机制分析
  • 批准号:
    9119026
  • 财政年份:
    2015
  • 资助金额:
    $ 38.41万
  • 项目类别:
Mechanistic Analysis of Cytokinesis in Eukaryotes
真核生物细胞分裂的机制分析
  • 批准号:
    10001538
  • 财政年份:
    2015
  • 资助金额:
    $ 38.41万
  • 项目类别:
Mechanistic Analysis of Cytokinesis in Eukaryotes
真核生物细胞分裂的机制分析
  • 批准号:
    10451747
  • 财政年份:
    2015
  • 资助金额:
    $ 38.41万
  • 项目类别:
Mechanistic Analysis of Cytokinesis in Eukaryotes
真核生物细胞分裂的机制分析
  • 批准号:
    10224222
  • 财政年份:
    2015
  • 资助金额:
    $ 38.41万
  • 项目类别:

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由两类细菌肌动蛋白 MreB 驱动的新型运动系统
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