Tuberous sclerosis complex (TSC) is characterized by hamartoma (benign tumor) formation in a wide range of tissues. TSC is caused by mutation in either the TSC1 (for 30% of the TSC cases) or TSC2 (for 60% of TSC cases) tumor suppressor gene. TSC1 and TSC2 protein bind to each other and form a functional complex. The major function of TSC1/TSC2 is to inhibit the activity of the Rheb protein, which is a positive regulator of mTOR (mammalian target of rapamycin). Therefore, mTOR activity is elevated in TSC mutant cells due to high Rheb activity. The high mTOR activity may be responsible for the uncontrolled growth in TSC. This hypothesis is supported by the observations that inhibition of mTOR by rapamycin significantly blocks TSC phenotypes in animal models. In fact, a clinical trial is under way using rapamycin to treat TSC-associated disease. The mTOR function is regulated by many conditions, including hypoxia (low oxygen). The major goal of this proposal is to study how mTOR activity is inhibited by low oxygen. The information generated in this study will help us to understand the abnormal cell growth of TSC cells, especially under low oxygen condition, and may be useful for future treatment of TSC and related diseases.