PURINE SYNTHESIS, DOWN'S SYNDROME, AND MENTAL RETARDATION

嘌呤合成、唐氏综合症和智力低下

• 批准号: 6240931
• 负责人: DAVID PATTERSON
• 金额: $ 19.9万
• 依托单位: ELEANOR ROOSEVELT INST FOR CANCER RES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 1998-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240931
• 关键词: Downs syndrome; aneuploidy; artificial chromosomes; enzyme activity; enzyme deficiency; gene expression; genetic regulation; genetically modified animals; human tissue; in situ hybridization; karyotype; laboratory mouse; mental retardation; miscellaneous oxidoreductase; purine /pyrimidine metabolism; purines; tissue /cell culture; transferase; trisomy

Defects in purine metabolism resulting in either increases or decreases in purine biosynthesis lead to mental retardation (MR) and a variety of other problems, including autism, behavioral abnormalities, sensorineural deafness, epilepsy, and gouty arthritis. Individuals with Down Syndrome (DS) have abnormal purine metabolism leading to 150% of normal purines in their bodily fluids, and a gene GART encoding a multifunctional protein carrying out 3 of the steps of de novo purine synthesis maps to chromosome 21. In no case is the pathogenetic mechanism for a disease due to a defect in purine metabolism known, and it is not known whether the elevated purine levels in individuals with DS has any other consequences. Molecular genetic mechanisms of regulation of cellular purine synthesis have not been studied, and no suitable animal models exist for the study of purine synthesis. We propose to address these problems by 1) assessing the role of molecular genetic regulation of cellular purine synthesis and especially the role of GART; 2) Study of purine synthesis in a new uricase deficient mouse created by Dr. Caskey for analysis of the health-related effects of aberrations in this pathway; 3) Study of purine synthesis using a partial trisomy 16 mouse constructed by Dr. Muriel Davisson which may have an extra copy of the mouse GART gene; 4) Construction and analysis of human GART expressing transgenic mice; 5) Analysis of the offspring of various combinations of the mice studied in 2-4 above. These studies should generate detailed knowledge of mechanisms of regulation of cellular and animal purine synthesis, an initial assessment of the role of regulation of purine synthesis in DS and other forms of MR and developmental disease, establishment of an animal model to study purine metabolic defects and DS, and should determine whether aberrant purine metabolism plays a significant role in establishment of the DS phenotype.

嘌呤代谢的缺陷导致增加或减少 在嘌呤生物合成中导致智力低下（MR）和各种各样 其他问题，包括自闭症，行为异常，感觉神经性 耳聋，癫痫和痛风关节炎。 患有唐氏综合症的人 （DS）具有异常的嘌呤代谢，导致150％的正常嘌呤 在他们的体液中，以及编码多功能的基因gart 从头嘌呤合成图的蛋白质进行了3个步骤 染色体21。在任何情况下，疾病的病毒机制绝不是 由于已知的嘌呤代谢缺陷，尚不清楚是否知道 DS患者的嘌呤水平升高还有其他 结果。 细胞调节的分子遗传机制 嘌呤合成尚未研究，也没有合适的动物模型 存在用于嘌呤合成的研究。 我们建议解决这些问题 问题1）评估分子遗传调节的作用 细胞嘌呤合成，尤其是Gart的作用； 2）研究 Caskey博士创建的新尿素不足的鼠标中的嘌呤合成 用于分析与健康相关的畸变作用 途径； 3）研究使用部分三体小鼠研究嘌呤合成的研究 由穆里尔·戴维森（Muriel Davisson）博士建造 小鼠Gart Gene； 4）表达人类Gart的构建和分析 转基因小鼠； 5）分析各种组合的后代 在上面的2-4中研究的小鼠。 这些研究应产生详细 了解细胞和动物嘌呤调节机制 合成，对嘌呤调节作用的初步评估 DS和其他形式的MR和发育疾病的合成， 建立动物模型来研究嘌呤代谢缺陷和 DS，应确定异常的嘌呤代谢是否发挥作用 在建立DS表型中的重要作用。