MOUSE MODELS OF DOWN SYNDROME--PHENOTYPIC MAPPING

这项研究计划的总体目标是发现 人类21号染色体额外拷贝的存在 (HSA 210产生DS的表型。 除了智力迟钝 和轻度畸形特征，这种表型的重要化合物是 阿尔茨海默病（AD）的神经退行性和功能变化，T- 淋巴细胞免疫缺陷，儿童白血病发生率增加，以及 先天性心脏病 爱泼斯坦博士的研究小组采用的方法是基于 前提是可以将相关的特定组件 三体表型与基因或基因组表达的增加有关， 基因存在于HSA 21上。 爱泼斯坦博士此前曾开创了重要的 16三体（Ts 16）小鼠作为DS动物模型的研究，以及 Ts 16模型是近年来发展起来的一个局部模型。 在这个建议中，一系列的方法来表型映射的两个 提出了部分和完整的Ts 16。 这些方法是减法 在性质上，最初，他们是基于对变化的分析， 通过端粒插入或照射， 将评估后代的哪些表型特征， 完整或部分Ts 16作为特定区域的额外拷贝消失， 染色体不再存在。 这样确定的区域将 进一步分析，以确定潜在的候选基因，和真正的作用， 这些区域和基因在产生三体性表型变化中的作用 通过转基因和同源重组技术建立。 为了实现这些目标，爱泼斯坦博士和他的同事们将产生小鼠 16号染色体进行性截短的Ts 16胚胎干细胞 (MMU)165），并分析表型（免疫，造血，中枢 神经系统）的部分Ts动物来源于这些细胞。 他和 同事们将进一步生成和表征Ts 16胚胎和胎儿， （来源于具有完整和截短的16号染色体的干细胞系） 在整体形态发生、生存力和基因表达方面， 中枢神经系统神经元，发展免疫和 造血系统和心脏形态发生。

The overall objective of this research program is to discover the mechanisms by which the presence of an extra copy of human chromosome 21 (HSA 210 produces the phenotype of DS. In addition to mental retardation and mild dysmorphic features, important compounds of this phenotype are the neurodegenerative and functional changes of Alzheimer's disease (AD), a T- lymphocyte immunodeficiency, increased frequency of childhood leukemia, and congenital heart disease. The approach Dr. Epstein's group uses is based on the premise that it will be possible to related specific components of the trisomic phenotype to the increased expression of genes or sets of genes present on HSA 21. Dr Epstein has previously pioneered important studies of the trisomy 16 (Ts16) mouse as an animal model of DS, and a partial Ts16 model has been developed recently by others. In this proposal, a series of approaches to the phenotypic mapping of both partial and complete Ts16 are proposed. These approaches are subtractive in nature initially in that they are based on the analysis of the changes of the trisomic region by telomere insertion or irradiation, the resulting progeny will be assessed with regard to which phenotypic features of complete or partial Ts16 disappear as extra copies of particular regions of the chromosome are not longer present. Regions so identified will then be analyzed further to identify potential candidate genes, and the true role of these regions and genes in producing phenotypic changes in trisomy established by transgenic and homologous recombination techniques. To accomplish these goals, Dr. Epstein and colleagues will generate mouse Ts16 embryonic stem cells with progressive truncations of chromosome 16 (MMU) 165) and analyze the phenotypic (immunologic, hematopoietic, central nervous system) of the partial Ts animals derived from these cells. He and colleagues will further generate and characterize Ts16 embryos and fetuses (derived from stem cell lines with complete and truncated chromosome 16s) with regard to overall morphogenesis, to the viability and gene expression of central nervous system neurons, to development of immune and hematopoietic systems, and to cardiac morphogenesis.