Rescuing the Fragile X Syndrome by Resetting Translational Homeostasis

描述(申请人提供)：脆性X综合征(FXS)是由于缺乏FMRP引起的，FMRP是mRNA翻译的负调控因子。在这个拟议的脆性X中心，Gary Bassell，Erick Klann和Joel Richter证明了改变翻译格局的分子的耗尽或抑制逆转了小鼠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，当药物失活时，它会恢复FXS(Bassell Project)中调控的蛋白质合成和树突棘的形态；p70S6 Kins1(S6K1)，当基因消融时，它会纠正FXS小鼠的分子、突触和行为表型(Klann Project)；以及细胞质多聚腺苷化元件结合蛋白(CPEB)，它的缺失可以挽救FXS的不适当蛋白质合成、突触失调和行为异常。这些发现为改变翻译格局和改善FXS症状提供了前所未有的机会。这个 首席研究人员将与RNA测序/生物信息学核心一起，使用创新的分子生物学来识别当PI3K、S6K和CPEB被消融或抑制时其翻译被挽救的mRNAs，这将定义FXS的潜在分子基础，并指示治疗该疾病的新疗法。研究人员将与电生理学/动物行为核心合作，评估被拯救的蛋白质合成如何调节突触效能和更高的认知功能。研究人员与这两个研究核心合作，探索可挽救的翻译的分子机制，并应用从FXS小鼠模型中获得的方法和知识来评估FXS在人类细胞中的分子原因。调查人员将与管理核心合作，以确保脆性X中心的科学卓越。

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.