Molecular requirements for proliferation of fetal and adult liver progenitors

描述（由申请人提供）：Notch通路的配体和受体已被确定为Allagille综合征（一种复杂的发育障碍）的致病因素。该综合征的一个显著特征是由胆管缺乏引起的胆汁淤积。一般来说，Notch信号是谱系承诺决定的关键分子成分，影响细胞相对于邻近细胞的成熟。因此，我们假设，在肝脏形态发生和/或再生过程中，Notch信号控制了祖细胞的谱系承诺和/或细胞命运决定，而祖细胞是肝脏胆道和血管结构形成的基础。这种结构的形成对正常肝功能至关重要。因此，本提案的总体目标是识别和定义在正常肝脏形态发生和成人肝脏再生过程中需要Notch信号形成肝脏结构的细胞系。提出了两个具体目标。在目的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Aim 2中，我们将使用小鼠模型来特异性删除内胚层和内皮细胞系中的Notch信号，确定Notch通路是否在肝母细胞祖细胞群的增殖和形态发生中起直接或间接的作用。这两个目标都将通过利用已有的小鼠模型来实现，这些模型可以实现谱系追踪和谱系特异性的Notch信号消融。

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.