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FMRP（mRNA翻译的负调节因子）缺失引起的。在这个提议的脆性X中心，加里巴塞尔，埃里克Klann和乔尔里希特证明，消耗或抑制分子，改变翻译景观逆转过度蛋白质合成和FXS病理生理表型在小鼠中。这些分子包括PI 3激酶，当PI 3激酶失活时，其恢复失调的蛋白质合成和表征FXS的树突棘形态（Bassell项目），p70 S6激酶1（S6 K1），其在基因消融时校正FXS小鼠所展示的分子、突触和行为表型（Klann项目）;和胞质多聚腺苷酸化元件结合蛋白（CPEB），其缺陷挽救了不适当的蛋白质合成，突触失调，和行为异常是FXS的显著特征这些发现提供了一个前所未有的机会来改变翻译景观和改善FXS的症状。的 主要研究者与RNA测序/生物信息学核心一起，将使用创新的分子生物学来鉴定当PI 3 K，S6 K和CPEB被消融或抑制时翻译被拯救的mRNA，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，评估拯救的蛋白质合成如何调节突触功效和更高的认知功能。研究人员与两个研究核心合作，探索拯救翻译的分子机制，并应用从FXS小鼠模型中获得的方法和知识来评估人类细胞中FXS的分子原因。研究人员将与行政核心合作，以确保脆性X中心的科学卓越性。

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.