Identification of Small Molecule Suppressors of Tsc Mutant Phenotypes in Drosophila

Principal Investigator: SU, TIN TIN
Institution Receiving Award: COLORADO, UNIVERSITY OF, BOULDER
Program: TSCRP
Proposal Number: TS093045
Award Number: W81XWH-10-1-0258
Funding Mechanism: Exploration - Hypothesis Development Award
Partnering Awards:
Award Amount: $141,737.00


Tuberous sclerosis (TS) is a heritable human disorder that includes the growth of benign tumors in many tissues including the brain, skin, kidney, and heart. TS 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 effect of mutations in Tsc genes. Previous work has shown that Tsc mutant cells in Drosophila show excessive growth and that mutant animals die as larvae. We will use these animals to screen through a large collection of chemicals (20,000 molecules). We are looking for molecules that reduce the death rate of mutant larvae and the excessive growth of mutant cells. Such molecules have the potential to suppress overgrowth of Tsc mutant tumors in human TS patients.