Molecular pathogenesis of autosomal recessive polycystic kidney disease (ARPKD): Fibrocystin as a regulator of cell metabolism and mitochondrial function

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Autosomal recessive polycysitc kidney disease (ARPKD) is a severe genetic disorder of early childhood that is typically characterized by intrauterine enlargement of fibrocystic kidneys resulting in early-onset end stage renal disease and obligatory hepatic involvement presenting as congenital hepatic fibrosis. The molecular pathogenesis of ARPKD and the cellular function of the affected protein fibrocystin (FC) remain incompletely understood. It has been suggested that FC may influence the same intracellular signaling cascades as the two proteins mainly affected in the more common autosomal dominant polycystic kidney disease (ADPKD). Overlapping clinical and genetic findings between ARPKD and ADPKD have been described.To gain insight into the molecular function of FC, we characterized various cellular models, including patient-derived cell lines and transgenic cell lines, and e.g. obtained cellular signatures by RNASeq and proteome analyses as well as mass spectromtry-based studies of the FC interactome. Findings from these experiments suggest that FC may, in addition to its function at the cellular cilium, contribute to the regulation of cellular metabolism. Celllular metabolic reprogramming has been described for ADPKD by various independent groups.In the suggested project we examine a potential link between FC and changes of the renal-tubular cell metabolism and mitochondria in ARPKD in detail and thus analyze whether cell metabolic processes could serve as a potential therapeutic target in ARPKD. By using CRISPR/Cas9-based PKHD1-deficient human cellular models we will characterize FC-dependent effects on general cellular aspects. We will then define specific metabolic signaling profiles and study mitochondrial function, morphology and protein composition. In an in vivo approach the role of Caveolin-1, a candidate for a FC-interacting protein identified in our previous work, for the renal and hepatic phenotype will be described by using a murine ARPKD modell and generating a double knockout mouse.In summary, the results of this project will give insights into the pathogenesis of ARPKD and may serve as a starting point for first targeted therapeutic strategies for one of the most devastating pediatric renal diseases.