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：
7652485
负责人：
Stacey S Huppert
金额：
$ 29.36万
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 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7652485
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 Chronic Complex DNA-Binding Proteins Data Defect Development Diet Embryo Embryonic Development Endoderm Endothelial Cells Endothelium Epithelial Cells Failure Genetic Genetic Recombination Goals Hepatic Hereditary Disease Injury Invertebrates Knowledge Lead Ligands Liver Liver Regeneration Liver diseases 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 developmental disease fetal insight liver cell proliferation migration mouse model notch protein novel oval cell progenitor response stem tool

项目摘要

DESCRIPTION (provided by applicant): Both ligand and receptors of the Notch pathway have been identified as the causative 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. Project Narrative: 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.

描述（由申请人提供）：Notch 通路的配体和受体均已被确定为 Allagille 综合征（一种复杂的发育障碍）的致病因素。该综合征的一个显着特征是胆管缺乏引起的胆汁淤积。一般来说，Notch 信号传导是影响细胞相对于邻近细胞成熟的谱系定型决策的关键分子组成部分。因此，我们假设肝脏形态发生和/或再生期间的Notch信号传导控制祖细胞的谱系定型和/或细胞命运决定，这些祖细胞是肝胆管和血管结构形成的基础。这种结构的形成对于正常的肝功能至关重要。因此，该提案的总体目标是鉴定和定义在正常肝脏形态发生期间和成人再生期间需要Notch信号传导来形成肝结构的细胞谱系。提出了两个具体目标。在目标 1 中，我们将识别并追踪在发育和成体肝脏再生过程中激活 Notch1 的细胞谱系。在目标 2 中，我们将使用专门删除内胚层和内皮细胞谱系中 Notch 信号传导的小鼠模型，确定 Notch 通路在肝母细胞祖细胞群的增殖和形态发生中是否发挥直接或间接作用。这两个目标将通过利用现有的小鼠模型来实现，这些模型能够进行谱系追踪和谱系特异性的 Notch 信号消融。项目叙述：这些研究具有重要意义，因为它们将确定成人肝脏发育及其再生过程中Notch激活的关键位点。我们获得的知识可能会及时增强我们治疗慢性肝病的能力，慢性肝病目前是美国第七大死因。