KNOCKOUT MODEL FOR CANAVAN DISEASE

卡纳万病的敲除模型

• 批准号: 6394109
• 负责人: REUBEN MATALON
• 金额: $ 28.6万
• 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 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394109
• 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（来自摘要）：缺乏天冬氨酸酰化酶（ASPA）和

项目成果

Novel splice site mutation of aspartoacylase gene in a Turkish patient with Canavan disease.

• DOI: 10.1053/ejpn.1999.0256
• 发表时间: 2000-01-01
• 期刊: European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society
• 作者: Rady, P L;Penzien, J M;Matalon, R
• 通讯作者: Matalon, R

Canavan disease prenatal diagnosis and genetic counseling.

卡纳万病产前诊断和遗传咨询。

• DOI: 10.1016/s0889-8545(01)00003-1
• 发表时间: 2002
• 期刊: Obstetrics and gynecology clinics of North America
• 影响因子: 3.2
• 作者: Matalon,Reuben;Matalon,KimberleeMichals
• 通讯作者: Matalon,KimberleeMichals

Expression of glutamate transporter, GABRA6, serine proteinase inhibitor 2 and low levels of glutamate and GABA in the brain of knock-out mouse for Canavan disease.

卡纳万病敲除小鼠大脑中谷氨酸转运蛋白、GABRA6、丝氨酸蛋白酶抑制剂 2 的表达以及低水平的谷氨酸和 GABA。

• DOI: 10.1016/s0361-9230(03)00158-8
• 发表时间: 2003
• 期刊: Brain research bulletin
• 影响因子: 3.8
• 作者: Surendran,Sankar;Rady,PeterL;Michals-Matalon,Kimberlee;Quast,MichaelJ;Rassin,DavidK;Campbell,GeraldA;Ezell,EdL;Wei,Jingna;Tyring,StephenK;Szucs,Sylvia;Matalon,Reuben
• 通讯作者: Matalon,Reuben