Dr. Eric Klann
Rescuing the Fragile X Syndrome by Targeting S6K1
This project investigates how inhibiting S6K1 rescues FXS phenotypes in mice. This project interfaces with Dr. Bassell’s project because S6K1 and PI3K are at least partially in the same signaling pathway. Three specific aims are proposed, the first of which is based on the data of Bhattacharya et al (2012) who showed that mice lacking FMRP and S6K1 are corrected to near WT. Here, they propose to test whether a small molecule inhibitor of S6K1 can reverse FXS when injected into FMRP KO adult animals. This aim interfaces with the electrophysiology/behavior core. The second aim is to use ribosome run-off/ribosome profiling to identify the mRNAs whose translation is rescued when S6K1 is either pharmacologically inhibited or genetically ablated. This aim integrates with Richter and the RB core. The final aim is to assess whether excessive S6K1 signaling in human iPSC-differentiated neurons contributes to exaggerated protein synthesis in these cells and to investigate resulting phenotypes. This aim interfaces with Bassell, who also will employ human FXS iPSCs and with the RB core