The Role of the Notch Pathway in Bile Duct Development

切迹通路在胆管发育中的作用

基本信息

  • 批准号:
    6958294
  • 负责人:
  • 金额:
    $ 36.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-09-15 至 2010-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Inherited disorders of intrahepatic bile duct development are a major cause of morbidity and mortality in the pediatric population. In recent years, advances have been made toward understanding the genetic control of liver development, but relatively little is understood regarding the molecular regulation of bile duct development. Identification of Jag1 as the disease gene for Alagille syndrome (AGS), an autosomal dominant disorder characterized by bile duct paucity along with anomalies in other organ systems, has revealed a crucial role for Jag1 and the Notch pathway in bile duct development. Jag1 encodes a ligand in the Notch signaling pathway, which is involved in cell fate determination in many organ systems. Homozygous targeted disruption of Jag1 in a mouse model causes early embryonic lethality, and the heterozygous mutant mouse has no phenotype. We have generated a Jag1 conditional knockout mouse using the Cre/lox gene targeting system. This model will permit the systematic study of the role of Jag1 in the development of multiple organ systems at specified times during development. Preliminary studies have demonstrated expression of Jag1 in the primitive bile ducts, or ductal plate cells, which originate from hepatocyte precursors in developing mouse and human liver. We propose to selectively ablate Jag1 in the developing liver and bile ducts by breeding the Jag1-loxP mouse with a liver-specific Cre transgenic line. Using this mouse model, we will perform detailed studies of ductal plate remodeling and bile duct development in the absence of Jag 1. In addition, we will employ real time PCR and micro array analysis to identify unique downstream targets of the Notch pathway in bile duct development. As a complementary strategy, we propose to use a cell culture approach in which we will derive bipotential hepatoblast cell lines from embryonic wildtype and Jag1 null livers. We will assess their response to defined stimuli, and rescue the phenotype by transfecting with activated Notch
描述(由申请人提供):肝内胆管发育的遗传性疾病是儿童发病率和死亡率的主要原因。近年来,在了解肝脏发育的遗传控制方面取得了进展,但对胆管发育的分子调控知之甚少。发现Jag1为Alagille综合征(AGS)的致病基因,揭示了Jag1和Notch通路在胆管发育中的重要作用。AGS是一种常染色体显性遗传病,以胆管缺乏和其他器官系统异常为特征。Jag1编码Notch信号通路中的一个配体,在许多器官系统中参与细胞命运的决定。在小鼠模型中,纯合子靶向破坏Jag1会导致早期胚胎致死,杂合子突变小鼠无表型。我们利用Cre/lox基因靶向系统产生了Jag1条件敲除小鼠。该模型将允许系统地研究Jag1在发育过程中特定时间的多器官系统发育中的作用。初步研究表明,Jag1在原始胆管或管板细胞中表达,这些细胞起源于发育中的小鼠和人类肝脏的肝细胞前体。我们建议通过培育具有肝脏特异性的Cre转基因系的Jag1- loxp小鼠来选择性地消融发育中的肝脏和胆管中的Jag1。使用该小鼠模型,我们将在没有jag1的情况下对胆管板重塑和胆管发育进行详细研究。此外,我们将采用实时PCR和微阵列分析来确定Notch通路在胆管发育中的独特下游靶点。作为补充策略,我们建议使用细胞培养方法,我们将从胚胎野生型和Jag1缺失的肝脏中获得双潜能肝母细胞系。我们将评估它们对特定刺激的反应,并通过转染激活的Notch来挽救表型

项目成果

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Kathleen Mary Loomes其他文献

Kathleen Mary Loomes的其他文献

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{{ truncateString('Kathleen Mary Loomes', 18)}}的其他基金

Training Program in the Genetic Basis of Pediatric Gastrointestinal Disorders
儿科胃肠道疾病遗传基础培训计划
  • 批准号:
    10633195
  • 财政年份:
    2014
  • 资助金额:
    $ 36.52万
  • 项目类别:
Training Program in the Genetic Basis of Pediatric Gastrointestinal Disorders
儿科胃肠道疾病遗传基础培训计划
  • 批准号:
    10452700
  • 财政年份:
    2014
  • 资助金额:
    $ 36.52万
  • 项目类别:
Training Program in the Genetic Basis of Pediatric Gastrointestinal Disorders
儿科胃肠道疾病遗传基础培训计划
  • 批准号:
    10200024
  • 财政年份:
    2014
  • 资助金额:
    $ 36.52万
  • 项目类别:
DNA methylation in biliary development and disease
胆道发育和疾病中的 DNA 甲基化
  • 批准号:
    8849898
  • 财政年份:
    2011
  • 资助金额:
    $ 36.52万
  • 项目类别:
DNA methylation in biliary development and disease
胆道发育和疾病中的 DNA 甲基化
  • 批准号:
    8676783
  • 财政年份:
    2011
  • 资助金额:
    $ 36.52万
  • 项目类别:
The Role of the Notch Pathway in Bile Duct Development
切迹通路在胆管发育中的作用
  • 批准号:
    8012164
  • 财政年份:
    2010
  • 资助金额:
    $ 36.52万
  • 项目类别:
The Role of the Notch Pathway in Bile Duct Development
切迹通路在胆管发育中的作用
  • 批准号:
    7485688
  • 财政年份:
    2005
  • 资助金额:
    $ 36.52万
  • 项目类别:
The Role of the Notch Pathway in Bile Duct Development
切迹通路在胆管发育中的作用
  • 批准号:
    7283571
  • 财政年份:
    2005
  • 资助金额:
    $ 36.52万
  • 项目类别:
The Role of the Notch Pathway in Bile Duct Development
切迹通路在胆管发育中的作用
  • 批准号:
    7123349
  • 财政年份:
    2005
  • 资助金额:
    $ 36.52万
  • 项目类别:
The Role of the Notch Pathway in Bile Duct Development
切迹通路在胆管发育中的作用
  • 批准号:
    7681058
  • 财政年份:
    2005
  • 资助金额:
    $ 36.52万
  • 项目类别:

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