Molecular requirements for proliferation of fetal and adult liver progenitors

Notch通路的配体和受体都被确定为致癌物 Allagille综合征的因素，一种复杂的发育障碍。一个与众不同的人 本综合征的特点是胆管稀少所致的胆汁淤积。凹槽 一般来说，信号是血统承诺的关键分子成分。 相对于邻近细胞影响细胞成熟的决定。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 构成形成基础的祖细胞的谱系承诺和/或细胞命运决定 肝脏、胆管和血管的结构。这一体系结构的形成至关重要 对正常的肝功能很重要。因此，这项提案的总体目标是 识别和定义需要Notch信号才能形成的细胞系 肝脏结构，无论是在正常肝脏形态发生期间还是在 成体的再生。提出了两个具体目标。在目标1中，我们将确定 并追踪在发育和成年肝脏中激活Notch1的细胞的谱系 再生。在目标2中，我们将确定Notch通路是直接还是 间接作用于肝母细胞前体细胞的增殖和形态发生 使用生成的鼠标模型专门删除中的Notch信号的种群 内胚层和内皮细胞谱系。这两个目标都将通过采取 利用已有的小鼠模型实现谱系追踪和谱系- Notch信号的特异性消融。这些研究具有重要意义，因为它们将确定Notch激活的关键部位(S 在成年人群的肝脏发育和再生过程中。这个 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， 这是目前美国第七大死因。

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.