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：
10541831
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/10541831
关键词：
3-Dimensional Adopted Adult Apical Architecture Back Beds Behavior Bile fluid Biliary Cell Lineage Cell division Cells Cellular Structures Cholangiocarcinoma Chronic Clinical Coupled Development Diameter Disease Duct (organ) structure E-Cadherin Embryo Epithelium Feedback Feeds Fibroblast Growth Factor Fibroblast Growth Factor Receptors Genetic Goals Hepatocyte Human Intercellular Junctions Intrahepatic bile duct Legal patent Life Ligands Link Liver Liver diseases Liver parenchyma Malignant - descriptor Malignant Neoplasms Modeling Morphogenesis Mutation Natural regeneration Organ Patients Process Proliferating Psychological reinforcement Publishing Reaction Research Personnel Role Runaway Shapes 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 pharmacologic 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.

项目概要肝内胆管树的作用是将肝细胞胆管中的胆汁排出肝脏。先天性或肝内胆管的形成和通畅性的获得性异常会导致严重的、通常是致命的结果。在发育中的肝脏中，胆道形态发生是一个自组织过程，其中双电位成肝细胞同时采取胆道命运并组织成无细胞的连续管状网络分配。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肝细胞。成人肝脏中的再生胆道形态发生和与疾病相关的异常胆道“导管反应”。协调胆道结构和命运以实现这种戏剧性形态发生的机制编程和构建功能性胆管树在很大程度上是未知的。了解胆道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。我们最近发现管腔从头形成扩张启动胆道形态发生，对于胆道结构和命运的协调至关重要。我们已发表的初步研究提出了一种模型，其中管腔形成产生物理信号反馈以加强胆道结构和命运的生态位，从而从由内而外。该项目的长期目标是了解管腔的形成和延伸如何指导胆管网络的形成。这项工作的成功完成将弥补我们在了解如何安全地构建这一重要器官，并在疾病中限制或修复它。