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

基本信息

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
项目类别：
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

项目摘要

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）：脆弱的X综合征（FXS）是由缺乏FMRP引起的，FMRP是mRNA翻译的负调节剂。在这个提出的脆弱X中心中，Gary Bassell，Erick Klann和Joel Richter表明，耗尽或抑制分子会改变小鼠中转化景观反向过度蛋白质合成和FXS病理生理表型。 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);以及细胞质聚腺苷酸化元件结合蛋白（CPEB），其缺乏促进了不适当的蛋白质合成，突触失调和行为异常，这是FXS的重要特征。这些发现为改变FXS的转化景观和改善症状提供了前所未有的机会。这主要研究人员以及RNA测序/生物信息学核心将使用创新的分子生物学来识别当PI3K，S6K和CPEB被灌输或抑制时，其翻译被挽救的mRNA，这将定义FXS的潜在分子基础，并指示FXS的潜在分子基础来治疗这种疾病。研究人员将与电生理/动物行为核心一起评估救出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，探索救出翻译的分子机制，并应用FXS小鼠模型所获得的方法和知识来评估人类细胞中FXS的分子因果关系。调查人员将与行政核心合作，以确保脆弱的X中心的科学卓越。