In vitro modelling of biliary development and diseases

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Bile is a toxic fluid produced in the liver and transferred through tubular structures known as bile ducts to the gut, where it helps with fat absorption. In bile duct disorders (cholangiopathies), the bile ducts fail to contain and transfer bile effectively. As a result, toxic bile leaks out of the ducts and accumulates in the liver causing significant damage. Unfortunately, our understanding of the exact mechanisms leading to biliary disease is very limited. Research in the field is hindered by technical difficulties in obtaining and maintaining live bile duct samples in the laboratory and the lack of animal models faithfully reproducing the disease. Nevertheless, the need to decipher the disease mechanisms, towards developing new diagnostic tests and treatment options is very pressing. Bile duct disorders account for a major proportion of all liver disease, carrying significant mortality. The only available treatment is liver transplantation, a lifesaving but expensive and challenging operation, requiring lifelong medication and follow-up and complicated by the national shortage of liver donors.Alagille syndrome (AGS) is an inherited disorder. Although it involves multiple organs, biliary disease caused by poor bile duct development in pregnancy and early life constitutes the most common clinical manifestation. Liver transplantation remains the only treatment option. Compared to other bile duct disorders the study of AGS has two important advantages: Primarily, the disease mechanism is not completely unknown, as the hereditary mutation causing it has already been described. Secondarily, in view of the close association between AGS and bile duct development, elucidating the disease mechanism will provide significant information on how bile ducts normally develop. Duct development is implicated to some extent in all childhood biliary disorders leading to paediatric liver transplantation. Therefore, studying AGS may advance our knowledge on a whole group of biliary diseases.The aim of this project is to develop a novel method for generating large amounts of fully functional bile duct replicas in the laboratory. The resulting ducts will provide an excellent model to study any biliary disease, test and develop new therapies. I propose applying this method for generating the first proof-of-principle disease model for AGS and elucidating the disease mechanism. I have already made significant progress towards achieving this goal. Using the technology of stem cells, I have successfully created functional bile duct replicas, starting from healthy individuals' skin samples. I intend to use the same approach to generate and study bile ducts from AGS patients. Once the ducts have been created, I will use cutting edge technology to decipher the series of events leading to AGS and attempt to 'rescue' the diseased ducts by intervening and altering these events.This project will shed light on the mechanisms driving AGS, facilitating the development of new tests for identifying the disease in early stages, new markers for predicting its course and new treatment options alternative to liver transplantation. Ultimately, it will contribute to improving the patients' quality of life, reducing pressure on the transplant waiting list and changing AGS from an untreatable disease to a manageable condition. Furthermore, the platform described has the potential to generate large amounts of bile duct replicas from patients with any biliary disorder. Therefore, it will provide a powerful novel disease modelling tool for the benefit of any research group working on bile ducts, overcoming the difficulties related to lack of biliary tissue and paving the road towards understanding and treating biliary disease in the future.