CHOLLID

Bile secretion is an essential function of the liver necessary for fat digestion and xenobiotic elimination. This function mainly rely on transporters localized at the canalicular membrane of hepatocytes, such as the ATP-binding cassette (ABC) transporters including ABCB4, ABCB11, responsible for the secretion of phosphatidylcholine (PC) lipids and bile salts into bile, respectively. Genetic variations of the loci encoding these two ABC transporters are correlated with rare cholestatic liver diseases, the most severe forms being progressive familial intrahepatic cholestasis (PFICs). Unfortunately, current pharmacological treatments remain inefficient or disappointing, the ultimate option for these patients remaining liver transplantation. Substantial efforts are thus required to develop alternative pharmacological therapeutic strategies. Our CHOLLID project focuses on clinically relevant ABCB4 and ABCB11 genetic variants that are associated with defects in their expression, traffic or function. The therapeutic challenge of CHOLLID, a bedside-to-bench-to-bedside project, is to characterize these variants at the molecular and cellular levels (structure, function, localization, molecular partners…), and to identify and develop new efficient targeted pharmacotherapies as an alternative for patients with severe forms of ABCB4- and ABCB11-related diseases. Such strategy is inspired from pharmacotherapies proposed for patients with cystic fibrosis, due to mutations in ABCC7/CFTR (cystic fibrosis transmembrane conductance regulator), but also from previous works of the coordinator to which the CHOLLID consortium gathers a broad range of expertise from the atomic scale to preclinical approaches. CHOLLID aims to develop a doctoral network that meets criteria of excellence in terms of training and science in the frame of the HORIZON-MSCA-2024-DN-01 call. For that, we are bringing together beneficiaries/partners with outstanding backgrounds in the various aspects of our project, from very basic in silico (molecular modeling, molecular dynamics…) and in vitro (cell models, organ-on-chips…) approaches to in vivo preclinical studies (mouse models mimicking the human pathologies), including innovative strategies (cryogenic electron microscopy, solid-state NMR, acellular in vitro functional assays…). So far, the enrolled beneficiaries have an excellent track record in their respective fields, ensuring a robust and valuable training for the recruited PhD candidates. These PhD candidates will be recruited in the frame of a fair, transparent and gender-equality process. During their PhD training, each candidate will have to opportunity to visit other labs of our consortium (“secondments” of up to six months on the overall PhD period) in order to benefit from different working environments, develop new skills and learn new techniques; these aspects are crucial for the excellence of our program and make it eligible under this MSCA-DN call. Moreover, non-academic beneficiaries/partners will be integrated in the consortium, allowing students to discover as many postdoctoral opportunities as possible. The basis of our consortium has already been settled and additional beneficiaries/partners still have to be confirmed/integrated. For that, we will have online meetings but we believe that in-person meetings are mandatory to discuss in details about our project and to finalize the building of a solid and coherent consortium. This will be done in a European capital/big city in a member state involved in this project. Organization and holding of such meeting(s) requires funding, which is the principal object of the present application to this ANR MRSEI call. In addition, part of this funding may be used to hire a private firm competent to improve and correct our application file.