Inside-out construction of the biliary system

项目摘要 肝内胆管树的功能是将胆汁从肝细胞小管排出肝脏。先天性或 获得性肝内胆管形成和通畅性异常具有严重的，通常是致命的， 后果在发育中的肝脏中，胆管形态发生是一个自组织过程， 成肝细胞同时接受胆汁命运并组织成连续管状网络而没有细胞 师.越来越多的证据表明，成熟肝细胞的转分化也可以产生正常的 成人肝脏中再生性胆管形态发生和异常疾病相关的胆管反应。 胆道结构和命运的协调机制，以制定这一戏剧性的形态发生 编程和构建功能胆道树在很大程度上是未知的。了解胆道疾病的机制基础 形态发生对于利用肝脏的再生潜力同时避免致命的 慢性和恶性肝病的后果。我们最近发现， 和扩张启动胆管形态发生，是协调胆管结构和命运的中心。 我们发表的和初步的研究表明，管腔形成产生了一个物理信号的模型， 小生境，反馈，以加强胆道结构和命运，从而创造胆道系统从 内而外这个项目的长期目标是了解管腔的形成和延伸是如何引导 胆管网的形成。这项工作的成功完成将解决我们在这方面的一个关键差距。 了解如何安全地构建这个关键器官，并在疾病中限制或修复它。

Project Summary The intrahepatic biliary tree functions to drain bile from hepatocytic canaliculi away from the liver. Congenital or acquired abnormalities in the formation and patency of intrahepatic bile ducts have severe, often fatal consequences. In the developing liver, biliary morphogenesis is a self-organizing process whereby bipotential hepatoblasts simultaneously adopt a biliary fate and organize into a continuous tubular network without cell division. Mounting evidence suggests that transdifferentiation of mature hepatocytes can also yield both normal regenerative biliary morphogenesis and abnormal disease-associated biliary `ductal reactions' in the adult liver. The mechanisms by which biliary architecture and fate are coordinated to enact this dramatic morphogenetic program and build a functional biliary tree are largely unknown. Understanding the mechanistic basis of biliary morphogenesis is necessary to harness the regenerative potential of the liver while avoiding the lethal consequences of chronic and malignant liver disease. We recently discovered that de novo lumen formation and expansion initiates biliary morphogenesis and is central to the coordination of biliary architecture and fate. Our published and preliminary studies suggest a model wherein lumen formation creates a physical signaling niche that feeds back to reinforce both biliary architecture and fate, thereby creating the biliary system from the inside out. The long-term goal of this project is to understand how lumen formation and extension guides the formation of the biliary tubular network. The successful completion of this work will address a key gap in our understanding of how to safely build this critical organ, and limit or repair it in disease.