Tuberous sclerosis (TSC) is a common autosomal dominant genetic disorder occurring in approximately 1/6000 of the population. TSC is characterized by the development of hamartomas in a wide range of human tissues. Common clinic symptoms include seizures, mental retardation, kidney failure, facial angiofibromas, and cardial rhabdomyomas. Mutation in either TSC1 or TSC2 gene is responsible for TSC. Recent genetic studies have indicated that TSC I/TSC2 are involved in cell growth control and function as tumor suppressors. The TSC1 and TSC2 proteins form a physical and functional complex in the cell. The long-tern objectives of this project are to identify critical cellular targets, which mediate the physiological functions of TSC I/TSC2 and to verify potential drug targets for TSC. The specific aims of this proposal are: 1. To demonstrate that TSC1 and TSC2 function through the mammalian target of rapamycin (mTOR); 2. To validate S6K as a key downstream effector of TSC1/ TSC2. Biochemical, molecular and cell biological approaches will be used to accomplish these specific aims. [unreadable] [unreadable]