SCREEN FOR FRAGILE X MUTATION EXPANSION IN A PRIMATE MODEL

灵长类动物模型中脆性 X 突变扩展的筛选

• 批准号: 8357254
• 负责人: PAUL J HAGERMAN
• 金额: $ 2.52万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357254
• 关键词: 5' Untranslated Regions; Affect; Age-Years; Animal Model; Anxiety; Behavior; Blood specimen; Brain; CGG repeat; CGG repeat expansion; California; Cells; Dementia; FMR1 Gene; FXTAS; Fragile X Mental Retardation Protein; Fragile X Premutation; Fragile X Syndrome; Funding; Gait Ataxia; Generations; Grant; Human; Individual; Inherited; Intention Tremor; Lead; Learning Disabilities; Macaca mulatta; Mental Retardation; Messenger RNA; Modeling; Molecular; Mutation; National Center for Research Resources; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear Inclusion; Primates; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Social Phobia; Source; Toxic effect; Transcriptional Regulation; Trinucleotide Repeats; United States National Institutes of Health; Woman; cost; genetic pedigree; human subject; male; neurodevelopment; nonhuman primate; trait

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Fragile X syndrome (FXS), the most common inherited form of mental retardation, arises in individuals with more than 200 CGG repeats in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. In humans, approximately 1 in 260 women is a carrier of the expanded (55 to 200; premutation) CGG repeat. We have identified a rhesus macaque pedigree with 7 subject carriers of an expanded CGG region in the premutation range. Human subject carriers of fragile X premutations express higher levels of FMR1-mRNA, between 2 to 10 fold in blood samples. The increased FMR1 expression can lead to cell toxicity over the years and be the cause of fragile X-associated tremor/ataxia syndrome (FXTAS), a newly described neurodegenerative disease. FXTAS often involves intention tremor, gait ataxia, and dementia, and affects at least 1/3 of males over 50 years of age who carry small CGG-repeat expansions of the FMR1. The neuropathological hallmark of FXTAS is the presence of intranuclear inclusions in neural cells, found in the brains of all individuals examined to date who had suffered from the neurodegenerative disorder. It has also been observed that premutation carriers often express lower levels of fragile X protein (FMRP) that presumably causes social phobia, autistic-like behavior, anxiety, OCD, psychotic traits and learning disability. This rhesus macaque pedigree represents the first animal model that spontaneously carries expanded triplet repeats. By examining the expression of the FMR1 gene and related proteins in this pedigree of non human primates, we expect to make progress in the understanding of the molecular mechanisms leading to the expansion of the CGG repeats in succeeding generations, which in humans leads to impaired neurodevelopment (FXS) as well as identifying factors involved in transcriptional regulation in premutation carriers, which can result in a toxic levels of FMR1-mRNA that are known to predispose to late onset neurodegeneration (FXTAS).

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 脆弱的X综合征（FXS）是最常见的智力低下遗传形式，是在脆弱的X智力低下1（FMR1）基因的5'未翻译区域中重复200多个CGG重复的个体中产生的。在人类中，大约有260名女性中约有1个是扩张（55至200; Premunt）CGG重复的载体。我们已经确定了一个恒河猕猴的血统 CGG区域处于预告范围。脆弱X预言的人类受试者载体表达了更高水平的FMR1-MRNA，在血液样本中2至10倍之间。多年来，FMR1表达增加会导致细胞毒性，并成为脆弱的X相关震颤/共济失调综合征（FXTA）的原因，这是一种新描述的神经退行性疾病。 FXTA通常涉及意图震颤，步态共济失调和痴呆症，并影响至少1/3岁以上的男性，这些男性携带FMR1的小CGG重复扩张。 FXTA的神经病理学标志是在神经细胞中存在核内夹杂物，这是迄今为止所有患有神经退行性疾病的人的大脑中发现的。还观察到，预先载人经常表达 较低水平的脆弱X蛋白（FMRP）可能导致社交恐惧症，自闭症行为，焦虑，强迫症，精神病性状和学习障碍。这种恒河猕猴的血统代表了第一个自发延伸三胞胎重复序列的动物模型。通过检查非人类灵长类动物的这一谱系中FMR1基因和相关蛋白的表达，我们希望在理解分子机制方面取得进展已知可以易于发作神经变性（FXTA）。