Tuberous Sclerosis (TSC) is a genetic disease syndrome manifested by multiple benign and debilitating tumors that is caused by mutations in the TSC1/TSC2 protein complex. There are approximately 40,000 patients with TSC in the United States alone, and 900,000 world-wide. Normal TSC1/TSC2 complexes integrate multiple cues to regulate the pro-growth kinase, the mammalian target of rapamycin complex 1 (mTORC1). Therefore, high mTORC1 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 effectors in the TSC/mTORC1 pathway may provide additional treatment options.

One central mechanism underlying tumor formation in TSC is uncontrolled protein synthesis by hyperactive mTORC1. We recently discovered that cells lacking TSC2 have increased protein synthesis but with reduced protein quality. We hypothesize that the imbalanced protein quality and quantity may contribute to TSC pathology. In addition, we found that the translation machinery is regulated by mTORC1 and the same mRNA may give rise to different protein products. The objectives of this proposal are to define translational re-programming and its implications in TSC.

The success of this project will lead to better understanding of protein synthesis by nutrient signaling. More important, the identification of novel protein products as a result of TSC/mTORC1 dysregulation will provide pivotal information for future TSC therapeutic development. For instance, we speculate that rapamycin and translation inhibitors may provide synergistic effects to achieve a more complete and durable response in TSC.