Rescuing the Fragile X Syndrome by Resetting Translational Homeostasis

描述（由申请人提供）：脆性X综合征（FXS）是由缺乏FMRP （mRNA翻译的负调节因子）引起的。在这个提议的脆性X中心，Gary Bassell， Erick Klann和Joel Richter证明，在小鼠中，改变翻译景观的分子的消耗或抑制可以逆转过度的蛋白质合成和FXS病理生理表型。这些分子包括PI3激酶，其在药理学上失活后可恢复FXS的失调蛋白合成和树突棘形态（Bassell项目），p70S6激酶1 (S6K1)，其在基因上切除后可纠正FXS小鼠显示的分子、突触和行为表型（Klann项目）；胞质聚腺苷化元件结合蛋白（CPEB），缺乏CPEB可挽救不适当的蛋白质合成、突触失调和行为异常，这些都是FXS的突出特征。这些发现提供了一个前所未有的机会来改变转译景观和改善FXS的症状。这个

DESCRIPTION (provided by applicant): 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.