Inside-out construction of the biliary system

Document text

Principal Investigator: ANDREA I MCCLATCHEY
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $353,684
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

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.

Terms: <21+ years old><3-D><3-D modeling><3-Dimensional><3D><3D modeling><Acquired Abnormalities><Acquired Abnormality><Adopted><Adult><Adult Human><Apical><Architecture><Back><Beds><Behavior><Bile><Bile Juice><Bile Tract><Bile fluid><Biliary><Biliary System><Biliary Tree><Birth Defects><Blastosphere><Brachydanio rerio><Cadherin-1><Cancers><Cell Body><Cell Communication and Signaling><Cell Components><Cell Junctions><Cell Lineage><Cell Signaling><Cell Structure><Cell division><Cells><Cellular Structures><Cholangiocarcinoma><Cholangiocellular Carcinoma><Chronic><Clinical><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Coupled><DNA Synthesis Factor><Danio rerio><Development><Diameter><Disease><Disorder><Dorsum><Duct><Duct (organ) structure><E-Cadherin><Embryo><Embryonic><Endothelial Cell Growth Factor><Engineering / Architecture><Epithelial Calcium-Dependent Adhesion Protein><Epithelial-Cadherin><Epithelium><FGF><FGF Receptors><FGF-R><FGFR><Feedback><Feeds><Fibroblast Growth Factor><Fibroblast Growth Factor Gene Family><Fibroblast Growth Factor Receptor Family><Fibroblast Growth Factor Receptors><Fibroblast Growth Regulatory Factor><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><Hepatic Cells><Hepatic Disorder><Hepatic Parenchyma><Hepatic Parenchymal Cell><Hepatocyte><Human><Intercellular Junctions><Intracellular Communication and Signaling><Intrahepatic bile duct><Investigators><Legal patent><Life><Ligands><Link><Liver><Liver Cells><Liver diseases><Liver parenchyma><Malignant><Malignant - descriptor><Malignant Neoplasms><Malignant Tumor><Modeling><Modern Man><Morphogenesis><Mutation><Natural regeneration><Oncogenesis><Organ><Patents><Patients><Preimplantation Embryo><Process><Proliferating><Psychological reinforcement><Publishing><Reaction><Regeneration><Reinforcement><Research Personnel><Researchers><Role><Runaway><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Surface><System><Testing><Time><Trees><Tube><Tubular><Tubular formation><Tumor-Derived><Uvomorulin><Work><Zebra Danio><Zebra Fish><Zebrafish><adulthood><biliary cancer><biliary tract><biological signal transduction><blastocyst><blastula><cholangiosarcoma><developmental><fetal><genome mutation><hepatic body system><hepatic disease><hepatic organ system><hepatopathy><in vivo><insight><intrahepatic><lateral line><liver disorder><malignancy><mechanical force><morphogenetic process><mutant><neoplasm/cancer><notch><notch protein><notch receptors><novel><pharmacologic><pre-implantation embryo><programs><quantitative imaging><recruit><regenerate><regeneration potential><regenerative><regenerative potential><repair><repaired><self organization><social role><spatial relationship><spatiotemporal><three dimensional><three-dimensional modeling><tool><trafficking><transdifferentiation><tumor><tumorigenesis>