Cell-cell adhesion-mediated signaling determines epithelial polarization in the liver
细胞间粘附介导的信号传导决定肝脏中的上皮极化
基本信息
- 批准号:9906924
- 负责人:
- 金额:$ 58.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-04 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsApicalArchitectureBackBile Duct EpitheliumBile fluidBiliaryBiological AssayBloodBlood Coagulation FactorBlood capillariesCadherinsCell PolarityCell membraneCell-Cell AdhesionCellsDataDuctal Epithelial CellE-CadherinEndocytosisEngineeringEnsureEpithelialEpithelial CellsEpitheliumGastrointestinal tract structureGatekeepingGlycogenHepatic TissueHepatocyteIntestinesKnowledgeLipidsLiverLiver diseasesMediatingMembraneMesenchymalMetabolicMicrotubule StabilizationMicrotubulesModelingMolecularMonomeric GTP-Binding ProteinsMorphologyN-CadherinNatural regenerationOrganOutcomePathway interactionsPhenotypePlus End of the MicrotubulePopulationProteinsPublishingRegulationRestRunningSignal TransductionSignaling MoleculeSiteSurfaceSystemTestingTissue StainsToxicologyTransplantationXenobioticsbile canaliculus structurebile ductblood filtercell typeepithelial to mesenchymal transitiongene therapyinterstitialliver developmentloss of functionnectinneglectnovel strategiesprotein degradationprotein protein interactionprotein transportstem cellstissue culturetraffickingvenule
项目摘要
ABSTRACT
The liver is our largest metabolic organ. It produces proteins, lipids, clotting factors and glycogen while
dispensing bile and detoxifying xenobiotics. In order to transport these different substances, a sophisticated
network of liver venules, capillaries and interstitial conduits has evolved. An essential feature of this network
are the lumen-forming epithelia that give rise to two major liver cell populations: (1) mature hepatocytes - the
main parenchymal cell type, and (2) bile duct cells. Hepatocytes form single-cell cords with a capillary-like
luminal network (bile canaliculi) running between them. In contrast, bile duct cells form tubules, each with a
central lumen that receives the content of the bile canaliculi that has formed next to hepatocytes. During initial
liver development and bouts of regeneration, both hepatocytes and bile duct cells are derived from a common
epithelial precursor. How hepatocytes and biliary epithelia obtain their unique morphological and functional
phenotypes from this common precursor is poorly understood. Indeed, because bile canaliculi are not readily
visible by conventional H&E tissue stain, the study of epithelial polarity in the liver has largely been neglected.
The resulting gap in our knowledge has greatly hindered our ability to better understand the molecular basis of
common liver diseases, which typically present with changes in lumen organization. It also severely limits our
ongoing efforts to engineer hepatic tissue that can be used for transplantation, toxicology and gene therapy
studies.
To tackle these issues, we have developed a unique tissue culture model to examine and explain how
hepatocyte and bile duct luminal phenotypes form. It strongly suggests lumen polarity is established in two
distinct steps. First, cell-cell adhesion triggers initial lumen formation at cell-cell contact sites. Second, luminal
stability is then modified through E-cadherin signaling. Strong E-cadherin signaling antagonizes these luminal
cell-cell contacts to determine a bile duct epithelium with a single apical surface. In contrast, weak E-cadherin
signaling fails to block these cell-cell contacts and as a result the default pathway ensures hepatocytic polarity
proceeds where multiple bile canaliculi can now form luminal junctions running between them.
This hypothesis is supported by published and preliminary data that we obtained by developing cell
systems in which the polarity phenotype can be switched. We have furthermore established stem cell-derived
biliary and hepatocyte primary cultures to compare signaling mechanisms in the two liver epithelial cell types
directly. It is expected that these novel approaches will enable us to understand the fundamental core
mechanisms that drive cell type-specification and polarity phenotypes in the liver.
摘要
项目成果
期刊论文数量(0)
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ANNE MUESCH其他文献
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{{ truncateString('ANNE MUESCH', 18)}}的其他基金
Cell-cell adhesion-mediated signaling determines epithelial polarization in the liver
细胞间粘附介导的信号传导决定肝脏中的上皮极化
- 批准号:
10678950 - 财政年份:2019
- 资助金额:
$ 58.98万 - 项目类别:
Cell-cell adhesion-mediated signaling determines epithelial polarization in the liver
细胞间粘附介导的信号传导决定肝脏中的上皮极化
- 批准号:
10446638 - 财政年份:2019
- 资助金额:
$ 58.98万 - 项目类别:
Par1-substrates responsible for CagA-mediated pathogenesis of Helicobacter pylori
Par1-底物负责 CagA 介导的幽门螺杆菌发病机制
- 批准号:
8658044 - 财政年份:2012
- 资助金额:
$ 58.98万 - 项目类别:
Par1-substrates responsible for CagA-mediated pathogenesis of Helicobacter pylori
Par1-底物负责 CagA 介导的幽门螺杆菌发病机制
- 批准号:
8508205 - 财政年份:2012
- 资助金额:
$ 58.98万 - 项目类别:
Par1-substrates responsible for CagA-mediated pathogenesis of Helicobacter pylori
Par1-底物负责 CagA 介导的幽门螺杆菌发病机制
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8372334 - 财政年份:2012
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$ 58.98万 - 项目类别:
EMK1 in kidney and hepatic epithelial cell polarity
EMK1在肾和肝上皮细胞极性中的作用
- 批准号:
7982631 - 财政年份:2009
- 资助金额:
$ 58.98万 - 项目类别:
Mechanisms of luminal protein targeting in kidney and hepatic epithelial cells
管腔蛋白靶向肾和肝上皮细胞的机制
- 批准号:
8505478 - 财政年份:2005
- 资助金额:
$ 58.98万 - 项目类别:
Mechanisms of luminal protein targeting in kidney and hepatic epithelial cells
管腔蛋白靶向肾和肝上皮细胞的机制
- 批准号:
8705495 - 财政年份:2005
- 资助金额:
$ 58.98万 - 项目类别:
Mechanisms of luminal protein targeting in kidney and hepatic epithelial cells
管腔蛋白靶向肾和肝上皮细胞的机制
- 批准号:
8238756 - 财政年份:2005
- 资助金额:
$ 58.98万 - 项目类别:
Mechanisms of luminal protein targeting in kidney and hepatic epithelial cells
管腔蛋白靶向肾和肝上皮细胞的机制
- 批准号:
8333972 - 财政年份:2005
- 资助金额:
$ 58.98万 - 项目类别:
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