Tuberous Sclerosis (TS) is a genetic disease syndrome manifested by multiple benign and debilitating tumors, that is caused by mutations in TSC1/TSC2 protein complex. There are approximately 40,000 patients with TSC in the United States alone, and 900,000 worldwide. Normal TSC1/TSC2 complexes integrate multiple cues to regulate the pro-growth kinase, the mammalian target of rapamycin (mTOR). Therefore, high mTOR activity promotes unregulated cell growth and likely contributes to tumor formation in TSC patients. Recent clinical trials have demonstrated the therapeutic value of rapamycin for TSC and associated diseases. However, rapamycin is not effectively killing tumor cells, and targeting multiple proteins in the TSC-mTOR pathway may provide additional treatment options. Recently, we have found that the stress-induced preferential translation of Hsp70 mRNA is deficient in cells lacking TSC2. Furthermore, the selective translation of Hsp70 mRNA does not respond to rapamycin. The objectives of this proposal are to define the pathway leading to translational regulation. Specifically, we will investigate features of some mRNAs that respond to TSC-mTOR differentially. In addition, we will apply a genome-wide approach to search for other targets of TSC-mTOR pathway involved in mRNA translation. The success of this project will lead to better understanding of mRNA translation by nutrient signaling. More important, the identification of novel targets of TSC-mTOR pathway will provide pivotal information for future TSC drug development.