The aim of this research project is to develop new approaches to the treatment of diseases resulting from mutations in the tuberous sclerosis complex (TSC) genes. TSC mutations lead to the formation of tumors in tissues including the brain, skin, kidneys, heart, and lungs and affect an estimated 1 in 6,000 to 10,000 births. Furthermore, disruption of TSC can produce varied neurological and cognitive deficits, representing the most severe features of TSC. The currently available approaches to treating TSC-related diseases are limited and generally block or slow down tumor growth, rather than killing the diseased cells. Therefore, there is an urgent need to develop new therapeutic strategies to treat TSC-related disease. The purpose of our work is to identify existing drugs known to be safe for use in humans that could be repurposed for treating TSC-related diseases either alone or in combination with existing treatments. We aim to test all genes currently targeted by Food and Drug Administration (FDA)-approved drugs to identify those that specifically kill cells with TSC mutations rather than simply slowing their growth. To achieve this goal, we will use state-of-the-art functional genomics methods in the fruit fly, Drosophila, a proven model to study TSC. We will then take findings from the Drosophila system to guide further experiments in mammalian cells to validate potential therapeutic drug targets, eventually leading to validation in humans. Given that FDA-approved drugs already exist for all genes that we are testing, this approach will allow rapid transfer of identified drug targets to applied therapeutic strategies in the clinic.