Fragile X Related Genes Mental Retardation/Development

脆性 X 相关基因 智力低下/发育

• 批准号: 6926682
• 负责人: David Loren Nelson
• 金额: $ 36万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-10 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6926682
• 关键词: circadian rhythms; disease /disorder model; embryonic stem cell; fragile X syndromes; gene interaction; gene redundancy; gene targeting; genetically modified animals; genotype; histology; injection /infusion; laboratory mouse; mental retardation; model design /development; mutant; phenotype; protein structure function

DESCRIPTION (provided by applicant): This application seeks renewed funding for a joint project between the Nelson, Oostra and Paylor groups to create and study mouse models for human Fragile X syndrome. Prior aims of the project sought to develop and perform initial characterization of mice carrying conditional (Cre-lox) alleles at each of the 3 FMR1-like genes present in the mouse genome. Progress has been excellent; Fxr2 knockouts have been characterized, and models carrying conditional alleles have been created for Fmr1 and Fxr1. Double knockouts of Fmr1 and Fxr2 have been created; these show enhanced phenotypes beyond those found in the single mutants. Moreover, a unique circadian rhythm defect has been observed in double knockouts-these animals are hyperactive and show no rhythm in light/dark or dark/dark cycles. Fxr1 loss of function results in neonatal lethality, while animals with reduced levels of Fxr1 are affected, but viable. Mouse models for the human Fragile X premutation-associated tremor ataxia syndrome (termed FXTAS) have also been developed and are being characterized. These models recapitulate several aspects of this late onset neurodegenerative disorder. These studies offer the opportunity to create and characterize mouse models for genetic disorders (Fragile X syndrome and FXTAS) that result from a common human mutation. Such models will allow the determination of a number of the functions of the FMR1 class of proteins, and provide a resource for other groups interested in utilizing such models to test hypotheses regarding Fmr1 function and the consequences of its absence, as well as the newly described FXTAS disorder. This renewal request seeks to continue these studies through the pursuit of the following specific aims: 1) Development of models and assays for testing FMR1 and paralog functions in mice. 2) Development and use of mouse models to determine the mechanistic basis of Fragile X-premutation-associated tremor ataxia syndrome. Successful completion of these aims will allow the definition of function and dysfunction in Fragile X syndrome and FXTAS.

描述（由申请人提供）：本申请寻求为纳尔逊，Oostra和Paylor小组之间的联合项目提供新的资金，以创建和研究人类脆性X综合征的小鼠模型。该项目的先前目标是开发和执行小鼠基因组中存在的3个FMR 1样基因中的每一个携带条件（Cre-lox）等位基因的小鼠的初始表征。进展非常好; Fxr 2敲除已被表征，并且已经为Fmr 1和Fxr 1创建了携带条件等位基因的模型。已经创建了Fmr 1和Fxr 2的双敲除;这些显示出超出在单突变体中发现的那些的增强的表型。此外，在双重敲除中观察到了独特的昼夜节律缺陷--这些动物过度活跃，在明/暗或暗/暗周期中没有表现出节律。Fxr 1功能丧失导致新生儿死亡，而Fxr 1水平降低的动物受到影响，但仍存活。人类脆性X基因前突变相关震颤共济失调综合征（称为FXTAS）的小鼠模型也已开发出来，并正在进行表征。这些模型概括了这种迟发性神经退行性疾病的几个方面。这些研究提供了创建和表征遗传性疾病（脆性X综合征和FXTAS）的小鼠模型的机会，这些疾病是由常见的人类突变引起的。这些模型将允许确定FMR 1类蛋白质的许多功能，并为其他有兴趣利用这些模型来测试关于Fmr 1功能及其缺失的后果以及新描述的FXTAS疾病的假设的小组提供资源。本次更新申请旨在通过追求以下具体目标继续这些研究：1）开发用于检测小鼠FMR 1和Parkinson功能的模型和试验。2)小鼠模型的开发和使用，以确定脆性X-前突变相关震颤共济失调综合征的机制基础。这些目标的成功完成将允许在脆性X综合征和FXTAS中定义功能和功能障碍。