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Molecular requirements for proliferation of fetal and adult liver progenitors

胎儿和成人肝脏祖细胞增殖的分子需求

基本信息

批准号：
8290443
负责人：
Stacey S Huppert
金额：
$ 4.81万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2012-08-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8290443
关键词：
Ablation Adult Affect Alagille Syndrome Animal Model Architecture Basement membrane Biliary Blood Vessels Cause of Death Cell Communication Cell Lineage Cell Maintenance Cell Maturation Cell Proliferation Cells Characteristics Chemical Injury Chemicals Cholestasis Complex DNA-Binding Proteins Data Defect Development Diet Embryo Embryonic Development Endoderm Endoderm Cell Endothelial Cells Endothelium Epithelial Cells Failure Genetic Genetic Recombination Goals Hepatic Hereditary Disease Injury Invertebrates Knowledge Lead Ligands Liver Liver Regeneration Maintenance Molecular Morphogenesis Mouse Strains Mus Mutation Natural regeneration Operative Surgical Procedures Partial Hepatectomy Pathology Pathway interactions Play Population Process Proliferating Proteins Pseudostratified Epithelium Relative (related person)Reporter Role Signal Transduction Site Stem cells Structure Surgical Injuries Syndrome Time Tissues United States Vertebrates bile duct cell motility chronic liver disease developmental disease fetal insight liver cell proliferation migration mouse model notch protein novel oval cell progenitor response stem tool

项目摘要

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.

Notch通路的配体和受体都已被确定为致病因子