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途径的配体和受体都被确定为复杂发育障碍Allagille综合征的病因因素。该综合征的一个显着特征是胆汁管的少量引起的胆汁淤积。通常，Notch信号传导是谱系投入决策的关键分子成分，这些决策相对于相邻细胞，影响细胞成熟。因此，我们假设肝形态发生和/或再生期间的缺口信号控制祖细胞的谱系承诺和/或细胞命运决策，这些决策是肝胆道和血管结构的形成。这种体系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在正常的肝形态发生和成年人的再生过程中识别和定义需要缺口信号以形成肝结构的细胞谱系。提出了两个具体目标。在AIM 1中，我们将确定并追踪在发育和成人肝脏再生过程中激活Notch1的细胞谱系。在AIM 2中，我们将确定Notch途径在使用用于在内胚层和内皮细胞谱系中特异性删除Notch信号传导的小鼠模型的肝类母细胞祖细胞种群的增殖和形态发生中扮演直接或间接作用。这两个目标都将通过利用预先存在的小鼠模型来实现，该模型可以实现谱系跟踪和Notch信号的谱系特异性消融。项目叙述：这些研究很重要，因为它们将在肝脏的发展及其在成人人群中的再生过程中定义凹槽激活的关键部位。我们获得的知识可能会及时增强我们治疗慢性肝脏疾病的能力，这是美国目前是美国第七大死亡原因。