CE17 - Recherche translationnelle en santé

Fighting Biliary ATresia from Deciphering Mechanisms to Novel Models and TreatMENts (BATMEN) – BATMEN

Submission summary

Biliary atresia (BA) is a severe uncurable paediatric liver disease manifested as a fibroinflammatory destruction of the biliary ducts. There are no drugs for BA making it the most common cause of liver transplantation in children. Despite its serious health impact and high socioeconomic cost, there is no consensus about the molecular mechanisms underlying failed cholangiocyte and hepatocyte homeostasis in BA. I propose interdisciplinary highly translational research program addressing an urgent need to understand BA disease and to develop pre-clinical models for testing potential drugs for BA TreatMENt (BATMEN). The BATMEN proposal builds on a solid foundation of my unpublished genomic (exome sequencing), transcriptomic (NanoString) and tissue expression analyses (immunohistological analyses) in patient liver samples as well as my first findings in novel animal model of BA. My genomic findings point to BA as a polygenic disease with patients carrying rare damaging gene variants converging on the pathway essential for cellular homeostasis. I hypothesise that these genomic defects may induce a loss of epithelial integrity and hepato-biliary tissue disorganization, representing unrecognized mechanisms of BA. First, I will establish whether expression of identified rare damaging gene variants has functional relevance. Second, I will develop novel cellular and animal pre-clinical models of BA. To this end the unique patient derived cholangiocyte and hepatocyte organoid 3D culture models as well as conditional mouse model in the entire hepatobiliary system will be developed. Third, the therapeutic efficacy of antifibrotic drug that has emanated from my preliminary findings will be tested in novel models of BA. On completion, the BATMEN project will bring advances in understanding the mechanisms driving to hepato-biliary fibrosis in BA that might lead to novel therapies in BA and potentially an array of other liver diseases.

Project coordination

Muriel Girard (Institut Necker Enfants Malades - Centre de médecine moléculaire)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INEM Institut Necker Enfants Malades - Centre de médecine moléculaire

Help of the ANR 311,767 euros
Beginning and duration of the scientific project: March 2023 - 36 Months

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