KNOCKOUT MODEL FOR CANAVAN DISEASE

卡纳万病的敲除模型

• 批准号: 2833675
• 负责人: REUBEN MATALON
• 金额: $ 21.58万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2833675
• 关键词: Jewish; amidohydrolases; aspartate; autosomal recessive trait; congenital brain disorder; developmental neurobiology; disease /disorder model; enzyme deficiency; gene mutation; gene targeting; genetic models; genetically modified animals; laboratory mouse; model design /development; neural degeneration; neurogenetics; neuropathology; phenotype; protein localization

DESCRIPTION (from Abstract): The deficiency of aspartoacylase (ASPA) and the accumulation of N-acetylaspartic acid (NAA) in Canavan disease (CD), was discovered in our laboratory in 1988. Since then we have diagnosed more than 170 patients with Canavan disease, of whom 2/3 are of Ashkenazi Jewish extraction. The carrier rate among Ashkenazi Jewish individuals as determined in our laboratory is 1/36, suggesting that Canavan disease is much more common, even in non-Jewish populations, than expected. Aspartoacylase was purified, and full length human, bovine and mouse ASPA cDNA have been isolated and the human ASPA gene has been localized to the short arm of chromosome 17. The purpose of this proposal is: 1) Create a mouse model for Canavan disease. The mouse ASPA gene has been characterized. Disruption in the coding sequence will be introduced for the purpose of the creation of a knock-out mouse. 2) Developmental and behavioral studies will be done so the phenotype of the knock-out mouse model will be determined. 2) Biochemical studies will measure urinary, blood and brain NAA. Brain ASPA activity will also be determined. Brain NAA will also be determined in vivo without sacrificing the animals, which would be important for possible future therapies. 4) Neuropathological parameter will be determined, in an attempt to define the onset of histopathological changes in the mouse brain. The exact cellular localization of aspartoacylase in brain is unknown, although it is in the white matter. The use of the transporter gene will allow for the cellular localization of ASPA. The animal model will be important in establishing the timing of clinical AM histopathological changes in the mouse. 5) The knock-out mouse will be used in future studies for determining the metabolic role of NAA in brain, for experimentation with enzyme therapy and gene therapy.

描述（摘要）：Aspartoacylase（Aspa）和 n-乙酰天冬事酸（NAA）在Canavan疾病（CD）中的积累， 1988年在我们的实验室发现。从那时起，我们已经诊断出 有170多名Canavan病患者，其中2/3是 Ashkenazi犹太人提取。 Ashkenazi犹太人的运营商率 我们实验室确定的个人是1/36，表明 即使在非犹太人人群中，Canavan病也更为普遍 超出预期。 纯化了天冬氨酸酶，并全长人，牛和小鼠 ASPA cDNA已被分离，人ASPA基因已定位 到17号染色​​体的短臂。该提议的目的是：1） 为Canavan病创建小鼠模型。鼠标ASPA基因已经 特征。将引入编码顺序中的中断 创建淘汰鼠标的目的。 2）发展和 将进行行为研究，以便敲除小鼠的表型 将确定模型。 2）生化研究将测量尿液， 血液和脑NAA。还将确定大脑ASPA活性。脑 NAA也将在不牺牲动物的情况下在体内确定 这对于可能的未来疗法很重要。 4） 将确定神经病理学参数，以定义 小鼠大脑组织病理学变化的开始。确切的 脑在大脑中的细胞定位是未知的，尽管 它是白质。转运蛋白基因的使用将允许 用于ASPA的细胞定位。动物模型将是 对于建立临床AM组织病理学的时间至关重要 鼠标的变化。 5）将来将使用淘汰鼠标 研究NAA在大脑中的代谢作用的研究，因为 酶治疗和基因疗法实验。