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.

本部分研究代谢异常 由于特定酶的剂量增加， 唐氏综合症中的表型，特别是那些影响 神经认知和感觉神经发育以及神经变性。 21号染色体基因参与嘌呤的相关途径， 叶酸和活性氧（ROS）代谢将被检查， 因为所有这些通路的突变都会导致神经功能缺损， 人类嘌呤和Ros基因的转基因和敲除小鼠 神经通路有发育异常，包括神经缺陷， 与途径改变的预期效应一致， 这也与在患有癌症的个体中观察到的人类表型一致。 突变的途径。在嘌呤中表达基因的转基因小鼠 在本供资期内获得了途径。具体 目的包括：1）表征转基因小鼠的表型 2）产生另外的转基因小鼠，其表达 编码ATP合酶亚基的人ATP 50基因和用于 羰基还原酶和这些小鼠的分析; 3）Ts 65 Dn- 尿酸酶缺陷型部分16三体小鼠作为更高的保真度 人类代谢的小鼠模型; 4）将4中产生的小鼠与 叶酸还原载体转基因小鼠的建立及叶酸还原载体对转基因小鼠的影响分析 这对Ts 65 Dn小鼠的表型的影响; 5）产生和分析 敲除小鼠中的四个基因（GART，ATP 50，CBR和SOD 1）， 区域三体的Ts 65 Dn小鼠和适当的育种， 确定将这些基因恢复到正常二倍体状态的效果; 6)分析大脑样本中研究基因的表达 来自患有和没有唐氏综合症的个体;以及7）评估 尿酸盐对活性氧代谢的作用，通过适当的小鼠杂交， ROS途径的改变和尿酸酶缺陷小鼠。这些 实验应该导致对这些作用的严格理解， 认知和神经发育的途径，以及 该通路中的基因在DS中起作用。