Generation of a mouse model for Familial Dysautonomia.

家族性自主神经功能障碍小鼠模型的生成。

• 批准号: 6979728
• 负责人: IOANNIS DRAGATSIS
• 金额: $ 7.03万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6979728
• 关键词: I kappa B beta; RNA splicing; behavior test; disease /disorder model; familial dysautonomia; gene expression; genetically modified animals; histopathology; in situ hybridization; laboratory mouse; messenger RNA; model design /development; neurophysiology; northern blottings

DESCRIPTION (provided by applicant): Familial Dysautonomia (FD) is an autosomal recessive disorder that affects 1/3,600 live births in the Ashkenazi Jewish population. This debilitating disorder is characterized by poor development, survival and progressive degeneration of the sensory and autonomic nervous system. Despite recent advances, the disorder is inevitably fatal, with only 50% of patients reaching the age 30. In FD the major haplotype (>98% of the FD cases), is associated with a T?C transition in position 6 of the donor splice site of intron 20 of the Ikbkap gene (which encodes the IKAP protein). This mutation results in the generation of an mRNA in which exon 20 is spliced out causing a frameshift and producing a truncated protein of 79kD. The normal function of IKAP as well as the mechanisms leading to the progressive degeneration of the nervous system in FD remain unknown. In our proposed studies we will 1) analyze the pattern of expression of Ikbkap in the mouse to identify the tissues where IKAP may play an essential role and 2) generate a mouse model for FD using two strategies: The first strategy consists in replicating the human point mutation in intron 20 of the mouse gene, which should in principle lead to the production of a truncated protein. Potential differences in splicing recognition between the two species may however interfere with the generation of an FD model using this approach. As an alternative strategy, we propose to generate a deletion of exon 20. These two mouse lines will be generated in parallel. A preliminary characterization of these mice will include behavioral, physiological and histopathological analyses. If a successful mouse model is generated it will be made available for the scientific community for further characterization and for testing potential therapeutic strategies.

描述（由申请人提供）：家族性动物障碍（FD）是一种常染色体隐性疾病，影响Ashkenazi犹太人人口的1/3,600活产。这种衰弱的疾病的特征是发展和自主神经系统的发展，生存和进行性变性不佳。尽管最近有进展，但这种疾病不可避免地致命，只有50％的患者达到30岁。在FD中，主要的单倍型（> 98％的FD病例）与Intron Intron 20的供体剪接位点的T？c转变有关IKBKAP基因的20个供体剪接部位（IKBKAP基因的20个供体剪接部位）（IKBKAP基因的IKAP蛋白质编码）。该突变导致产生一个mRNA，其中外显子20被剪接，引起移率并产生79KD的截短蛋白质。 IKAP的正常功能以及导致FD神经系统进行性变性的机制尚不清楚。在我们提出的研究中，我们将1）分析IKBKAP在小鼠中的表达模式，以识别IKAP可能起重要作用的组织，并且2）使用两种策略生成小鼠模型：第一种策略是复制小鼠基因内含子20的人类点突变，这些策略应主要导致截止蛋白质的产生。但是，两种物种之间剪接识别的潜在差异可能会使用这种方法干扰FD模型的产生。作为另一种策略，我们建议生成外显子20的缺失。这两种鼠标系将并行生成。这些小鼠的初步表征将包括行为，生理和组织病理学分析。如果生成成功的鼠标模型，将为科学界提供进一步的表征和测试潜在的治疗策略。