Neuro-biliary talk
Financiado
Innervation-driven mechanisms of bile duct development
While liver development is well-studied, the signal initiating tubulogenesis of bile ducts therein remains to be identified. Neurites are present in the liver before bile duct tubulogenesis, and in other organs, innervation can in...
While liver development is well-studied, the signal initiating tubulogenesis of bile ducts therein remains to be identified. Neurites are present in the liver before bile duct tubulogenesis, and in other organs, innervation can instruct tubulogenesis. However, a role for liver innervation in biliary tubulogenesis has not been shown. Preliminary data from my host lab suggest a strong link between both processes: Defective biliary tubulogenesis caused by Notch mutations in Alagille syndrome (ALGS) is preceeded by a lack of liver innervation. I will test the hypothesis that intrahepatic innervation initiates biliary tubulogenesis.
First, I will apply 3D staining and imaging techniques to study the establishment of intrahepatic innervation at multiple timepoints during development, and quantify characteristics of innervation in healthy and ALGS mice in depth using automated image analysis. Secondly, I will investigate if liver innervation is required for tubulogenesis by performing nerve ablation studies and analyzing its effect on biliary cells. Finally, I will establish a method to perform transcriptional profiling of liver innervation. The liver is only innervated by nerve endings from extrinsic neurons, and these neurons have their cell bodies in ganglia outside of the organ where also other neurons reside. It has thus not been possible to isolate these cells from the liver and analyse their expression profiles. Using a viral barcode library to label neurons and their axon endings, I will perform single-cell RNA sequencing on those ganglia, and identify and characterize the cells innervating the liver.
Enabling expression profiling of extrinsic nerves will be a game changer in the field of organ innervation, and can be applicable to numerous other fields. This project will provide fundamental insights into the developmental functions of liver innervation and the molecular mechanisms underlying biliary tubulogenesis, providing a basis for future therapeutics.
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Duración del proyecto: 38 meses
Fecha Inicio: 2022-06-07
Fecha Fin: 2025-08-31
Fecha Fin: 2025-08-31
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2022-06-07
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
HORIZON-MSCA-2021-PF-01-01:
MSCA Postdoctoral Fellowships 2021
Cerrada
hace 3 años
Presupuesto
El presupuesto total del proyecto asciende a
207K€
Líder del proyecto
KAROLINSKA INSTITUTET
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5