Knock-in Mice with Spinocerebellar Ataxia Type 13 Mutations in Kcnc3 (Kv3.3) Gene

具有 Kcnc3 (Kv3.3) 基因 13 型脊髓小脑共济失调突变的敲入小鼠

基本信息

批准号：
8622223
负责人：
Diane M Papazian
金额：
$ 7.62万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8622223
关键词：
Action Potentials Adult Age Aging Alzheimer&apos s Disease Animal Model Animals Ataxia Atrophic Autistic Disorder Bacterial Artificial Chromosomes Basic Science Behavior Biological Biological Models Brain Breeding C57BL/6N Mouse California Cerebellum Chromosomes Communities Complex Development Disease ES Cell Line Electroporation Embryo Escherichia coli Etiology Funding Genes Genomics Genotype Grant Growth Health Human Infant Intellectual functioning disability Knock-in Mouse Laboratories Letters Melissa Modeling Morphology Motor Motor Neurons Movement Disorders Mus Mutation Neurodegenerative Disorders Neurons Onset of illness Parkinson Disease Pathogenesis Phenotype Plasmids Point Mutation Recombinants Reporting Research Research Personnel Resources Role Southern Blotting Spinocerebellar Ataxias Structure Time Transgenic Mouse Facility Transgenic Organisms Translating Universities Voltage-Gated Potassium Channel Zebrafish arm blastocyst clinical phenotype disease-causing mutation early childhood early onset embryonic stem cell homologous recombination human disease in vivo infancy locomotor deficit motor deficit neuron development neuronal excitability novel novel therapeutic intervention public health relevance research study stem synaptic function tool vector

项目摘要

DESCRIPTION (provided by applicant): This R03 project will generate two lines of knock-in mice with point mutations in the endogenous Kcnc3 gene, which encodes the Kv3.3 voltage-gated K+ channel. In humans, the analogous KCNC3 mutations cause distinct forms of spinocerebellar ataxia type 13 (SCA13). SCA13 is a rare autosomal dominant disease characterized by substantial atrophy of the cerebellum and locomotor deficits. Depending on the causative mutation, SCA13 presents as an early-onset neurodevelopmental disease or as an adult-onset neurodegenerative disease. The developmental form of SCA13 is evident in infancy or early childhood with intellectual disability, motor delay, persistent motor deficits, and severe cerebellar atrophy. The degenerative form of SCA13 emerges in adulthood with progressive ataxia accompanied by progressive loss of cerebellar volume. The product of the disease gene, Kv3.3, is highly expressed in fast-spiking cerebellar neurons, where it is an essential regulator of excitability. Disease-causing mutations alter Kv3.3 function, suggesting that changes in action potential firing trigger pathogenesis in SCA13. As a monogenic disorder, SCA13 provides an excellent opportunity to investigate the role of excitability in neuronal health and survival, and o identify mechanisms that translate altered excitability into pathogenic changes during development and aging. Animal models are essential to determine the consequences of SCA13 mutations in vivo and to investigate how different mutations in the same gene give rise to distinct clinical phenotypes. To identify mechanisms that contribute to pathogenesis in SCA13, a mammalian model system in which brain development, structure, and function are closely related to humans is crucial. Kcnc3 knock-in mice will provide essential tools for investigating the etiology of SCA13 and for translating the results of basic research into new therapeutic approaches for neurodevelopmental and neurodegenerative diseases. The knock-in mice generated in this project will be the first genetically accurate models of SCA13 in a mammalian model system. They will be made freely available as a resource for the research community. During the two year term of the R03 grant, we propose to accomplish the following Specific Aims: 1) to generate targeting vectors encoding the SCA13 adult- onset R421H or infant-onset F449L mutations in the mouse Kcnc3 gene; 2) to generate two lines of knock-in mice; and 3) to begin to characterize the phenotypes of the knock-in animals.

描述（由申请人提供）：该R03项目将在内源性KCNC3基因中生成两行敲入小鼠，该基因kcnc3基因编码Kv3.3电压门控k+通道。在人类中，类似的kCNC3突变引起了不同形式的脊髓脑性共济失调（SCA13）。 SCA13是一种罕见的常染色体显性疾病，其特征是小脑和运动缺陷的大量萎缩。根据病因突变，SCA13作为早期神经发育疾病或成人发作神经退行性疾病表示。 SCA13的发育形式在婴儿期或幼儿期具有智力障碍，运动延迟，持续运动缺陷和严重的幼儿期很明显小脑萎缩。 SCA13的退化形式在成年期出现，进行性共济失调伴随着小脑体积的进行性损失。该疾病基因Kv3.3的产物在快速刺激的小脑神经元中高度表达，它是兴奋性的必不可少的调节剂。引起疾病的突变改变了Kv3.3功能，表明动作电势发射的变化触发了SCA13中的发病机理。作为一种单基因疾病，SCA13提供了一个极好的机会来研究兴奋性在神经元健康和生存中的作用，并且o确定了将兴奋性转化为发育和衰老期间致病性变化的机制。动物模型对于确定体内SCA13突变的后果至关重要，并研究同一基因中不同的突变如何产生不同的临床表型。为了确定有助于SCA13发病机理的机制，SCA13是一种哺乳动物模型系统，其中脑发育，结构和功能与人类密切相关。 KCNC3敲入小鼠将提供研究SCA13病因的重要工具，并将基础研究结果转化为神经发育和神经退行性疾病的新治疗方法。该项目中产生的敲入小鼠将是哺乳动物模型系统中SCA13的第一个遗传准确模型。它们将免费作为研究界的资源。在R03赠款的两年期间，我们建议实现以下特定目的：1）生成编码SCA13成人发作R421H或婴儿kCCNC3基因中的sca13成人 - 成人发作R421H或婴儿发作的F449L突变的靶向矢量； 2）生成两条敲入小鼠； 3）开始表征敲击动物的表型。