Project Title Rescuing Fragile X Syndrome by Targeting p70 S6 Kinase 1 Abstract Fragile X syndrome (FXS) is caused by the lack of fragile X mental retardation protein, a negative regulator of translation. We previously showed that mTORC1 signaling, as measured by phosphorylated p70 S6 kinase 1 (S6K1) and elF4E-elF4G interactions, is elevated in FXS model mice. We then found that genetic ablation of S6K1 could correct molecular, synaptic/ and behavioral phenotypes displayed by the FXS mice. These findings have laid the groundwork for this proposal, where our central hypothesis is that excessive activation of S6K1 is a causative factor in the molecular, synaptic, and behavioral abnormalities in FXS. To test this hypothesis, we propose to 1) determine whether the S6K1 inhibitor PF-4708671 reverses phenotypes displayed by FXS model mice, 2) determine whether inhbition/deletion of S6K1 corrects exaggerated translation by reducing ribosome transit time in FXS model mice, and 3) determine whether excessive activation of S6K1 contributes to exaggerated translation and increased RTT in cells from FXS patients. These studies have the potential to identify new therapeutic targets for the treatment of FXS, and by extension, other developmental disabilities

Public Health Relevance

Fragile X syndrome (FXS) is the most commonly inherited cause of intellectual disability and autism. In this proposal we describe experiments designed to determine whether S6K1 can be a therapeutic target to reverse exaggerated protein synthesis, synaptic dysfunction, and aberrant behaviors displayed by FXS model mice.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54HD082013-01
Application #
8795363
Study Section
Special Emphasis Panel (ZHD1-DSR-Y (53))
Project Start
2014-09-22
Project End
2019-05-31
Budget Start
2014-09-22
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$378,211
Indirect Cost
$16,875
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655