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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：
8549380
负责人：
Stacey S Huppert
金额：
$ 23.5万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-07 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8549380
关键词：
Molecular requirements proliferation fetal adult

项目摘要

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.

Notch途径的配体和受体都已被确定为 Allagille综合征是一种复杂的发育障碍。一个显著这种综合征的特征是胆管缺乏引起的胆汁淤积。凹口一般来说，信号传导是谱系定型的关键分子组成部分，影响细胞相对于邻近细胞成熟的决定。因此，我们假设肝脏形态发生和/或再生期间的Notch信号传导控制着肝脏的形态发生和/或再生。形成基础的祖细胞的谱系定型和/或细胞命运决定肝胆管和血管结构的变化。这种结构的形成至关重要，对正常肝功能很重要。因此，本提案的总体目标是识别和定义需要Notch信号传导以形成在正常肝形态发生期间和成年人的再生。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Notch 1的细胞谱系再生在目标2中，我们将确定Notch通路是否发挥直接或间接的作用。间接参与肝祖细胞的增殖和形态发生使用产生的小鼠模型特异性地删除细胞中的Notch信号传导，内胚层和内皮细胞谱系。这两个目标将通过以下方式实现：预先存在的小鼠模型的优势，使谱系追踪和谱系- Notch信号传导的特异性消融。这些研究意义重大，因为它们将确定Notch激活的关键位点在成年人的肝脏发育和再生过程中。的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，目前是美国第七大死因。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A faithful JAGGED1 haploinsufficiency mouse model of arteriohepatic dysplasia (Alagille syndrome) after all.

毕竟是忠实的 JAGGED1 单倍体不足小鼠模型，是动脉肝发育不良（Alagille 综合征）的模型。

DOI：
10.1002/hep.28338
发表时间：
2016
期刊：
Hepatology (Baltimore, Md.)
影响因子：
0
作者：
Huppert,StaceyS
通讯作者：
Huppert,StaceyS

Defects in hepatic Notch signaling result in disruption of the communicating intrahepatic bile duct network in mice.

DOI：
10.1242/dmm.005793
发表时间：
2011-05
期刊：
Disease models & mechanisms
影响因子：
4.3
作者：
Sparks EE;Perrien DS;Huppert KA;Peterson TE;Huppert SS
通讯作者：
Huppert SS

Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice.

DOI：
10.1002/hep.23431
发表时间：
2010-04
期刊：
HEPATOLOGY
影响因子：
13.5
作者：
Sparks, Erin E.;Huppert, Kari A.;Brown, Melanie A.;Washington, M. Kay;Huppert, Stacey S.
通讯作者：
Huppert, Stacey S.

Emerging advancements in liver regeneration and organogenesis as tools for liver replacement.

DOI：
10.1097/mot.0000000000000365
发表时间：
2016-12
期刊：
Current opinion in organ transplantation
影响因子：
2.2
作者：
Huppert SS;Campbell KM
通讯作者：
Campbell KM

Vascular patterning sets the stage for macro and micro hepatic architecture.

DOI：
10.1002/dvdy.24222
发表时间：
2015-03
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
0
作者：
Cast AE;Walter TJ;Huppert SS
通讯作者：
Huppert SS