Tuberous Sclerosis Complex (TSC) is a heritable human disorder that includes the growth of benign tumors in many tissues including the brain, skin, kidney, and heart. TSC occurs due to mutations in one of two genes, Tsc1 and Tsc2. The fruit fly, Drosophila melanogaster, has been especially useful for studying how Tsc1 and Tsc2 genes work and how their mutation produces tumors. We know now that Tsc1/Tsc2 normally act to suppress cellular growth (increase in mass). Constitutive loss of Tsc1 or Tsc2 through mutations then would lead to excessive growth, which could explain the benign tumors in TS patients.
We propose to use Drosophila melanogaster to screen for small molecules that can reverse the overgrowth of tissues with mutations in Tsc genes. We will first create Drosophila mutants that carry Tsc mutations in the eye. Previous work has shown that such animals show excessive growth of eye tissue that is easily discernable. We will use these animals to screen a large collection of chemicals (approximately 3,000 molecules) from the National Cancer Institute. We are looking for molecules that reduce the excessive growth Tsc mutant eyes in Drosophila. Such molecules have the potential to suppress overgrowth of Tsc mutant tumors in human TSC patients.