Disease mechanism and pharmacological approaches for TBC1D8B-induced steroid resistant nephrotic syndrome

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022

Nephrotic syndromes (NS) are a combinations of symptoms that can lead, in both children and young adults, to kidney dysfunction and increased risk to progress toward end-stage kidney disease. Steroid treatment allows remission of NS’s symptomatology in almost 90% of NS patients. However, for the remaining 10% such therapeutic treatment is useless, thus indicating the occurrence of the steroid-resistant nephrotic syndrome (SRNS).

Extensive research in the SRNS pathogenesis have proven that in over 30% of people affected by SRNS symptomatology the cause of the disease is hereditary (i.e., dysfunctional genes transmitted from parents to their children). Such pathogenic genetic variants comprise proteins expressed by specialized kidney cells named podocytes which are responsible to maintain the structural integrity of the kidney filtering apparatus. Despite several advances, the understanding of the biological role of genetic alterations causing SRNS is still difficult, thus limiting the identification of novel therapeutic options for SRNS.

Using innovative techniques, this research project aims at identifying pathways responsible for SRNS and at characterizing novel functional and pharmacologic interactions, to offer novel therapeutic opportunities for SRNS patients. To this end, we will focus on mutations of TBC1D8B, a gene with unknown function that was recently described to cause hereditary SRNS. By finding both novel genes and pathways involved in function of pathogenic TBC1D8B variants, we will provide insight into alternative signaling routes that may be targeted for future SRNS therapies.