PURINE, FOLATE, AND REACTIVE OXYGEN METABOLISM AND DOWN SYNDROME

该组件研究代谢异常的假设 由于增加特定酶的剂量可能会导致一些 唐氏综合征的表型，尤其是那些影响 神经认知和感觉神经发育和神经退化。 21号染色体上的基因参与了嘌呤的相互联系的途径， 将检查叶酸和活性氧(ROS)代谢， 因为所有这些途径的突变都会导致神经功能障碍 人类。转基因和基因敲除小鼠改变为嘌呤和ROS 通路有发育异常，包括神经缺陷， 与路径改变的预期效果和 也与人类的表型一致，在患有 这些途径中的突变。在嘌呤中表达基因的转基因小鼠 在本供资期间已经获得了途径。特定的 目的包括：1)转基因小鼠的表型特征 已获得；2)创建更多表达该基因的转基因小鼠 编码三磷酸腺苷合成酶亚基的人ATP50基因和 3)Ts65Dn-Ts65的构建 尿酸酶缺陷型部分三体16小鼠作为保真度较高的小鼠 人类新陈代谢的小鼠模型；4)将4年中创建的小鼠与 还原型叶酸载体转基因小鼠及其干预效果分析 这是关于Ts65Dn小鼠的表型；5)创造和分析 中的四个基因(GART、ATP50、CBR和SOD1)被敲除的小鼠 Ts65Dn小鼠的区域三聚体及其选育 确定将这些基因恢复到正常二倍体状态的效果； 6)分析正在研究的基因在大脑样本中的表达 来自患有和不患有唐氏综合症的个人；以及7)评估 尿酸对小鼠适当杂交后ROS代谢的影响 ROS途径和尿酸酶缺陷小鼠的变化。这些 实验应该导致对这些因素的作用有一个严格的理解 认知和神经发育的途径以及三体是否 该途径中的基因在DS中起着作用。

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.