PURINE, FOLATE, AND REACTIVE OXYGEN METABOLISM AND DOWN SYNDROME

嘌呤、叶酸和活性氧代谢与唐氏综合症

• 批准号: 6301897
• 负责人: DAVID PATTERSON
• 金额: $ 17.74万
• 依托单位: ELEANOR ROOSEVELT INST FOR CANCER RES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6301897
• 关键词: Downs syndrome; adenosine triphosphate; brain mapping; chromosome 21; diploidy; disease /disorder model; enzyme activity; enzyme deficiency; folate; free radical oxygen; gene expression; gene mutation; gene targeting; genetically modified animals; human tissue; hydroxymethyltransferases; laboratory mouse; miscellaneous oxidoreductase; phenotype; polymerase chain reaction; purine /pyrimidine metabolism; purines; trisomy; urate; vitamin metabolism

This component investigates the hypothesis that metabolic abnormalities due to increased dosages of specific enzymes may cause some of the phenotypes seen in Down Syndrome, especially those affecting neurocognitive and sensorineural development and neurodegeneration. Chromosome 21 genes involved in the interrelated pathways of purine, folate, and reactive oxygen species (ROS) metabolism will be examine, because mutations in all these pathway lead to neurological deficits in humans. Transgenic and knockout mice altered to the purine and Ros pathways have developmental anomalies, including neurological deficits, consistent with the expected effects of alteration of the pathways and also consistent with the human phenotypes seen in individuals with mutations in the pathways. Transgenic mice expressing genes in the purine pathways have been obtained during the current funding period. Specific aims include: 1) characterization of the phenotypes of the transgenic mice already obtained; 2) creation of additional transgenic mice expressing the human ATP50 gene encoding a subunit of ATP synthase and the human gene for carbonyl reductase and analysis of these mice; 3) creation of Ts65Dn- uricase deficient partial trisomy 16 mouse to serve as a higher fidelity mouse model of human metabolism; 4) crossing the mice created in 4 with the reduced folate carrier transgenic mice and analysis of the effect of this on the phenotype of the Ts65Dn mouse; 5) creation and analysis of knockout mice for four of the genes (GART, ATP50, CBR, and SOD1) in the region trisomeric in the Ts65Dn mouse and appropriate breeding of these to determine the effect of restoring these genes to the normal diploid state; 6) analysis of the expression of the genes under study in brain samples from individuals with and without Down Syndrome; and 7) assessment of the role of urate on ROS metabolism by appropriate crosses of mice with alterations in the ROS pathway and the uricase deficient mice. These experiments should result in a rigorous understanding of the role of these pathways in cognition and neural development and whether trisomy of the genes in the pathway plays a role in DS.

该组成部分研究了代谢异常的假设 由于特定酶的剂量增加可能会导致某些 在唐氏综合症中看到的表型，尤其是那些影响的表型 神经认知和感觉神经性发育和神经变性。 与嘌呤相互关联的途径涉及的21个基因， 叶酸和活性氧（ROS）代谢将被检查， 因为所有这些途径的突变导致神经缺陷 人类。转基因和敲除小鼠变为嘌呤和ROS 途径具有发育异常，包括神经缺陷， 与途径改变的预期影响一致 也与患有人的人类表型一致 路径中的突变。在嘌呤中表达基因的转基因小鼠 在当前资金期间已获得途径。具体的 目的包括：1）转基因小鼠表型的表征 已经获得； 2）创建表达的其他转基因小鼠 人ATP50基因编码ATP合酶亚基和人类基因的亚基 这些小鼠的羰基还原酶和分析； 3）创建TS65DN- 尿液酶缺乏部分三体三体16小鼠可作为更高的保真度 人类代谢的小鼠模型； 4）跨越4与4的小鼠 叶酸载体转基因小鼠的减少和分析 这是关于TS65DN小鼠的表型的； 5）创建和分析 四个基因（GART，ATP50，CBR和SOD1）的敲除小鼠 TS65DN小鼠中的三化区域，并将其适当的育种 确定将这些基因恢复到正常二倍体状态的效果； 6）分析脑样品中研究基因的表达 来自有和没有唐氏综合症的人； 7）评估 尿酸尿酸盐对ROS代谢的作用与小鼠的适当交叉 ROS途径和Uricase缺乏小鼠的改变。这些 实验应导致对这些作用的严格理解 认知和神经发展的途径以及是否 途径中的基因在DS中起作用。