Investigating the role of TFEB in Tuberous Sclerosis associated-kidney pathology using novel kidney organoid models.

Tuberous sclerosis (TSC) is a genetic disorder caused by mutations in the TSC1 and TSC2 genes, characterized by the growth of benign tumors (hamartomas) in various organs such as the brain, heart, skin, lung, and kidney. Kidney complications are particularly concerning, with TSC-related kidney disease being a leading cause of mortality in affected adults. Recent data suggest that TFEB, a key regulator of cell metabolism, plays a crucial role in the kidney phenotype of TSC. Studies utilizing kidney organoids, three-dimensional cell cultures that mimic kidney tissue, have elucidated new mechanisms underlying TSC-related kidney pathology; however, they have some limitations. The TSC-kidney organoids developed thus far do not perfectly replicate the human kidney pathology, characterized by the presence of scattered lesions and cysts in the kidney due to second-hit mutations in the TSC genes. Here, we intend to utilize novel TSC kidney organoid models, which more closely resemble how TSC manifests in the human kidney, to investigate, in a time-dependent manner, the role of TFEB in kidney cystogenesis and tumorigenesis and to assess TFEB as a potential novel therapeutic target in TSC.