Rescuing the Fragile X Syndrome by Resetting Translational Homeostasis

通过重置转化稳态来拯救脆性 X 综合征

• 批准号: 8793364
• 负责人: Joel D Richter
• 金额: $ 189.51万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793364
• 关键词: 1-Phosphatidylinositol 3-Kinase; Animal Behavior; Animal Disease Models; Animal Model; Autistic Disorder; Base Sequence; Behavior; Behavioral; Bioinformatics; Brain; CPE-binding protein; Caliber; Cells; Data; Dendritic Spines; Disease; Electrophysiology (science); Ensure; Etiology; FMRP; Foundations; Fragile X Syndrome; Functional disorder; Genes; Genetic Translation; Goals; Head; Health; Homeostasis; Human; Inherited; Intellectual functioning disability; International; Investigation; Knowledge; Laboratories; Leadership; Massachusetts; Messenger RNA; Methods; Molecular; Molecular Biology; Morphology; Mus; New York; Patients; Phenotype; Phosphotransferases; Physiology; Principal Investigator; Protein Biosynthesis; Proteins; RNA Sequences; Research; Research Personnel; Science; Symptoms; Synapses; Syndrome; Tissues; Translations; Universities; Work; base; cognitive function; design; innovation; medical schools; mouse model; novel; novel therapeutic intervention; relating to nervous system; research study; therapeutic target

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.

描述（由申请人提供）：脆性 X 综合征 (FXS) 是由于 FMRP（mRNA 翻译的负调节因子）的缺失引起的。在这个拟议的脆弱 X 中心，Gary Bassell、Erick Klann 和 Joel Richter 证明，改变翻译景观的分子的消耗或抑制可以逆转小鼠体内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，可恢复失调的蛋白质合成和树突棘形态，这是 FXS 的特征（Bassell 项目）；p70S6 激酶 1 (S6K1)，当基因消除时，可纠正 FXS 小鼠表现出的分子、突触和行为表型 (Klann项目）;以及细胞质多腺苷酸化元件结合蛋白（CPEB），其缺陷可以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 的显着特征。这些发现为改变翻译景观和改善 FXS 症状提供了前所未有的机会。这 首席研究员与 RNA 测序/生物信息学核心一起，将利用创新的分子生物学来识别 mRNA，当 PI3K、S6K 和 CPEB 被消除或抑制时，这些 mRNA 的翻译可以被挽救，这将定义 FXS 的潜在分子基础，并为治疗 FXS 提供新的治疗方法。治疗疾病。研究人员将与电生理学/动物行为核心合作，评估获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，探索挽救翻译的分子机制，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 的分子因果关系。研究人员将与行政核心合作，确保 Fragile X 中心的科学卓越性。