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Inside-out construction of the biliary system

胆道系统由内而外的构建

基本信息

批准号：
10319945
负责人：
ANDREA I MCCLATCHEY
金额：
$ 36.84万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319945
关键词：
3-Dimensional Address Adopted Adult Apical Architecture Back Beds Behavior Bile fluid Biliary Caliber Cell Lineage Cell Shape Cell division Cells Cellular Structures Cholangiocarcinoma Chronic Clinical Coupled Development Disease Duct (organ) structure E-Cadherin Embryo Epithelial Feedback Feeds Fibroblast Growth Factor Fibroblast Growth Factor Receptors Genetic Goals Hepatocyte Human Instruction Intercellular Junctions Intrahepatic bile duct Life Ligands Link Liver Liver diseases Liver parenchyma Malignant - descriptor Malignant Neoplasms Modeling Morphogenesis Mutation Natural regeneration Organ Patients Pharmacology Process Psychological reinforcement Publishing Reaction Research Personnel Role Runaway Signal Transduction Structure Surface System Testing Time Trees Tube Tubular formation Tumor-Derived Work Zebrafish biliary tract blastocyst fetal in vivo insight intrahepatic lateral line mechanical force mutant notch protein novel programs quantitative imaging recruit regeneration potential regenerative repaired self organization spatial relationship spatiotemporal three-dimensional modeling tool trafficking transdifferentiation tumor tumorigenesis

项目摘要

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.

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。