Both ligand and receptors of the Notch pathway have been identified as the causitive factors in Allagille syndrome, a complex developmental disorder. A distinguishing characteristic of this syndrome is cholestasis brought on by paucity of bile ducts. Notch signaling, in general, is a critical molecular component for lineage commitment decisions that affect cell maturation relative to neighboring cells. Thus, we hypothesize that Notch signaling during hepatic morphogenesis and/or regeneration controls the lineage commitment and/or cell fate decisions of progenitor cells that underlie formation of the hepatic biliary and vascular architecture. Formation of this architecture is vitally important for normal hepatic function. Thus, the overall goal of this proposal is to identify and define the cell lineages that require Notch signaling for formation of the hepatic architecture, both during normal hepatic morphogenesis and during regeneration in the adult.
Two specific aims are proposed.
In Aim 1 we will identify and trace the lineage of cells that activate Notch1 during development and adult liver regeneration.
In Aim 2 we will determine whether the Notch pathway plays a direct or indirect role in the proliferation and morphogenesis of the hepatoblast progenitor cell population using mouse models generated to specifically delete Notch signaling in the endoderm and endothelial cell lineages.
Both Aims will be achieved by taking advantage of pre-existing mouse models that enable lineage tracing and the lineage- specific ablation of Notch signaling. These studies are significant in that they will define the key site(s) of Notch activation during both the development of the liver and its regeneration in adult populations. The knowledge we gain may, in time, enhance our ability to treat chronic liver diseases, which are currently the 7th leading cause of death in the United States.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078640-05
Application #
8290443
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Doo, Edward
Project Start
2008-07-15
Project End
2012-08-06
Budget Start
2012-07-01
Budget End
2012-08-06
Support Year
5
Fiscal Year
2012
Total Cost
$48,131
Indirect Cost
$14,274
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Huppert, Stacey S (2016) A faithful JAGGED1 haploinsufficiency mouse model of arteriohepatic dysplasia (Alagille syndrome) after all. Hepatology 63:365-7
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Cast, Ashley E; Walter, Teagan J; Huppert, Stacey S (2015) Vascular patterning sets the stage for macro and micro hepatic architecture. Dev Dyn 244:497-506
Walter, Teagan J; Cast, Ashley E; Huppert, Kari A et al. (2014) Epithelial VEGF signaling is required in the mouse liver for proper sinusoid endothelial cell identity and hepatocyte zonation in vivo. Am J Physiol Gastrointest Liver Physiol 306:G849-62
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Humphreys, Ryan; Zheng, Wei; Prince, Lawrence S et al. (2012) Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients. Hum Mol Genet 21:1374-83

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