Molecular requirements for proliferation of fetal and adult liver progenitors

描述(由申请人提供)：Notch途径的配体和受体都已被确定为Allagille综合征的致病因素，这是一种复杂的发育障碍。该综合征的一个显著特征是胆管稀少引起的胆汁淤积。一般说来，Noch信号是影响细胞相对于邻近细胞成熟的谱系承诺决定的关键分子成分。因此，我们假设，肝脏形态发生和/或再生过程中的Notch信号控制着祖细胞的谱系承诺和/或细胞命运决定，这是肝脏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，这项建议的总体目标是确定和定义需要Notch信号来形成肝脏结构的细胞系，无论是在正常的肝脏形态发生期间还是在成人的再生过程中。提出了两个具体目标。在目标1中，我们将鉴定和追踪在发育和成人肝脏再生过程中激活Notch1的细胞谱系。在目标2中，我们将利用在内胚层和内皮细胞系中特异性删除Notch信号的小鼠模型来确定Notch通路在肝母细胞前体细胞群体的增殖和形态发生中是否起直接或间接的作用。这两个目标都将通过利用现有的小鼠模型来实现，这些模型支持谱系追踪和特定谱系的Notch信号消融。 项目简介：这些研究具有重要意义，因为它们将确定成年人群肝脏发育及其再生过程中Notch激活的关键部位(S)。随着时间的推移，我们获得的知识可能会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。

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.