Intracellular trafficking in kidney development and pathophysiology

Different inherited kidney diseases, such as Lowe Syndrome (caused by mutation in OCRL gene), Dent disease (CLCN5), Fabry disease (GLA) and Cystinosis (CTNS) are characterized by common clinical manifestations. Within the kidney, defective proximal tubule reabsorption of proteins, amino acids, vitamins and solutes is a common hallmark of such diseases, whose pathogenetic mechanisms are far from being completely unravelled and understood. The convergence towards similar clinical phenotypes among patients with mutations in these genes is rarely associated with the involvement of the same cellular pathway. This highlights important unsolved questions such as why proximal tubule are so fragile and why mutations in four different genes with diverse functions result in a very similar clinical outcomes. Since most of these disease-causative genes play key roles in different branches of intracellular membrane trafficking (endocytosis, lysosomal function, autophagy), we will investigate the contribution of these processes to kidney development and pathophysiology, combining Systems Biology, in vitro and in vivo approaches. We will investigate the way the membrane trafficking system is regulated during kidney development, by which mechanisms it regulates kidney morphogenesis and how and why the deregulation of different steps of membrane trafficking leads to similar cell-specific pathological alterations. The end goal is to identify common deregulated mechanisms that could represent points for therapeutic intervention. Furthermore, to deeply decipher the sub-tissue specificity of pathological manifestations and to develop new pharmacological approaches for human genetic kidney diseases, we will take advantage of the gold standard technology of kidney organoids. These models will be used to analyse cell specific transcriptional and translational programs in physiological and pathological conditions and will be exploited in drug and viral vector screening experiments, with the aim to pave the way towards new therapeutic approaches for genetic kidney diseases that are currently incurable. The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from January 2022 until last budget year, calculated based on the size of the research group.