Molecular requirements for proliferation of fetal and adult liver progenitors

描述（由申请人提供）：Notch途径的配体和受体均已被确定为Allagille综合征（一种复杂的发育障碍）的致病因素。这种综合征的一个显著特征是胆管缺乏引起的胆汁淤积。Notch信号传导通常是影响细胞相对于邻近细胞成熟的谱系定型决定的关键分子组分。因此，我们假设Notch信号传导在肝形态发生和/或再生过程中控制着构成肝胆管和血管结构形成基础的祖细胞的谱系定型和/或细胞命运决定。这种结构的形成对于正常的肝功能至关重要。因此，本提案的总体目标是鉴定和定义在正常肝形态发生期间和在成人再生期间需要Notch信号传导以形成肝结构的细胞谱系。提出了两个具体目标。在目标1中，我们将识别和追踪在发育和成人肝再生过程中激活Notch 1的细胞谱系。在目标2中，我们将使用产生的小鼠模型来确定Notch途径在肝母细胞祖细胞群体的增殖和形态发生中是否起直接或间接作用，以特异性地删除内胚层和内皮细胞谱系中的Notch信号传导。这两个目的将通过利用预先存在的小鼠模型来实现，所述小鼠模型能够进行谱系追踪和谱系特异性的Notch信号传导消除。 项目叙述：这些研究的意义在于，它们将确定成年人群中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提高我们治疗慢性肝病的能力，慢性肝病目前是美国第七大死亡原因。

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.