Fragile X syndrome (FXS) is caused by the absence of FMRP, a negative regulator of mRNA translation. In this proposed Fragile X Center, Gary Bassell, Erick Klann, and Joel Richter demonstrate that depletion or inhibition of molecules that alter the translational landscape reverse excessive protein synthesis and FXS pathophysiological phenotypes in mice. These molecules include PI3 kinase, which when pharmacologically inactivated restores dysregulated protein synthesis and dendritic spine morphology that characterize FXS (Bassell Project), p70S6 kinase 1 (S6K1), which when genetically ablated corrects molecular, synaptic and behavioral phenotypes displayed by FXS mice (Klann Project);and the cytoplasmic polyadenylation element binding protein (CPEB), whose deficiency rescues inappropriate protein synthesis, synapse dysregulation, and behavioral abnormalities that are prominent features of FXS. These discoveries provide an unprecedented opportunity to alter the translational landscape and ameliorate symptoms of FXS. The Principal Investigators, together with an RNA Sequencing/Bioinformatics Core, will use innovative molecular biology to identify mRNAs whose translation is rescued when PI3K, S6K, and CPEB are ablated or inhibited, which will define the underlying molecular basis of FXS and indicate novel therapies to treat the disease. The investigators will work with an Electrophysiology/Animal Behavior Core to assess how rescued protein synthesis regulates synapse efficacy and higher cognitive function. The investigators work with both research cores to explore molecular mechanisms of rescued translation and apply the methods and knowledge gained from mouse models of FXS to assess molecular causation of FXS in human cells. The investigators will work with an Administrative Core to ensure scientific excellence in the Fragile X Center.

Public Health Relevance

Fragile X Syndrome (FXS) is the most commonly inherited cause of intellectual disability and autism. In this proposed Center we describe experiments designed to determine how S6K1, P13K, and CPEB and their downstream mRNA targets can be used as therapeutic targets to reverse exaggerated protein synthesis synaptic dysfunction, and aberrant behaviors in FXS model mice and in human patients afflicted with the disease.

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 #
8793364
Study Section
Special Emphasis Panel ()
Program Officer
Urv, Tiina K
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
$1,895,126
Indirect Cost
$409,734
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655