Crosstalk between mTORC1 and cAMP Signaling

Principal Investigator: GUAN, KUN-LIANG
Program: TSCRP
Proposal Number: TS120072
Award Number: W81XWH-13-1-0055
Funding Mechanism: Idea Development Award
Partnering Awards:
Award Amount: $658,341.96


Mutations in either TSC1 or TSC2 gene are found in the majority of TSC patients and directly contribute to this disease. The key function of TSC1 and TSC2 is to inhibit cell growth. This is accomplished by the ability of TSC1/TSC2 to inhibit a kinase called mTORC1. In TSC1 or TSC2 mutant cells, mTORC1 activity is abnormally high, causing tumor growth. Therefore, drugs that can inhibit mTORC1 activity may be beneficial for TSC treatment. In fact, clinical trials have demonstrated that rapamycin, which inhibits mTORC1, has a beneficial effect on TSC-related diseases, such as the LAM disease. However, the effectiveness of rapamycin is limited, possibly because rapamycin does not completely inhibit all mTORC1 functions. Some functions of mTORC1 are not inhibited by rapamycin.

This proposal will study the mechanism of mTORC1 inhibition by cyclic adenosine 3'5' monophosphate (cAMP). cAMP was discovered six decades ago to play an important role in physiological regulation. This proposal will also study whether increasing cAMP can inhibit mTORC1 and cell growth of TSC mutant cells. Our preliminary data strongly support this possibility. If this hypothesis proves to be correct, then drugs that can increase cAMP may be valuable to treat TSC and related diseases. Luckily, there are many Food and Drug Administration-approved drugs that increase cellular cAMP. Because many of the cAMP-enhancing drugs have a long history of clinical use, the safety data of these drugs are readily available. This project will be completed in 3 years. Completion of this project will generate valuable scientific data for testing cAMP-enhancing drugs as a TSC therapy. Therefore, this project will have a direct impact on TSC patient care. Ten years ago, Dr. Guan's laboratory first reported that TSC1/TSC2 functions to inhibit mTOR. This exciting observation provided the initial scientific basis for clinical trials of using rapamycin for TSC treatment. The Principal Investigator is equally excited about this project and believes that completion of this project will create a similar impact in TSC research and therapy.