Periodic Report Summary 2 - RARITOR (mTOR pathophysiology in rare human diseases)
The mTOR pathway is a fundamental mechanism linking nutrition with growth, metabolism and ageing in eukaryotic cells. The overall goal of our research proposal is twofold. From one hand we want to better understand fundamental processes including cell size control and organismal longevity. To this end we want to determine the molecular targets of the mTORC1/S6 kinase cassette that may explain the alterations in cell size and lifespan when these kinases are deregulated. We developed a chemical genetic approach that led to the identification of new S6K targets regulating the senescence program (Barilari et al., 2017). From the other hand, we want to understand and cure rare human genetic diseases that arise from pathological changes in the activity of the mTOR pathway or that may benefit from therapeutical intervention on this pathway. These diseases include Tuberous Sclerosis Complex (TSC), PEComas and hemangiomas, metabolic diseases, lysosomal storage diseases. We identified YAP, PPARg,and class III PI3K, respectively, as therapeutic targets in TSC, steatosis-associated liver cancer, and lysosomal storage disease (Liang et al., 2014; Patitucci et al., 2017; Nemazanyy et al., 2015).