BA represents a huge medico-societal problem, improved diagnosis and new therapies are therefore urgently warranted. The root cause for lack of progress in BA treatment lies in the poor knowledge of its underlying pathogenetic mechanisms. We are a new BA consortium, which comprises a team of clinicians/scientists, strengthened by the addition of international experts with unique complementary expertise, who are poised to pioneer BA research, diagnosis and therapy.  Building on our promising discoveries recently published in Journal of Hepatology, we propose to advance BA research to improve our understanding of its disease mechanisms using novel, beyond state-of-the-art organoid-based systems, dissect disease heterogeneity through genomics and transcriptomics, and pursue novel therapeutic leads with pre-clinical testing.

These goals will be achieved by a multi-pronged approach. We will

1) use cholangiocyte organoids from human livers/induced Pluripotent Stem Cells, multi-cell type organoids, and cells/organoids seeded onto liver extracellular matrix-derived gel to assess the pathobiological roles of various cell types, paracrine/guidance/matrix cues, toxins, virus, immune-inflammatory dysfunction and fibrosis;

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2) integrate whole-exome (BA trios) and tissue transcriptomic analyses with comprehensive clinical/phenotype information to stratify BA patients and discover novel disease mechanisms;

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3) pursue targeted therapies, using BA organoids as clinical surrogates to test drug repurposing on amyloid-beta deposition, ciliary dysfunction (our new findings); immune-inflammation and fibrosis. The findings will inform clinicians on patient stratification and provide evidence for implementing clinical trials of novel therapies towards regeneration of a functional biliary tree. In sum, by combining leading clinical expertise and cutting-edge technologies, we will break new grounds in the understanding of a devastating liver disease and enhance its diagnostics and therapy development.