MOUSE MODELS OF DOWN SYNDROME--PHENOTYPIC MAPPING

这项研究计划的总体目标是发现 人类21号染色体额外拷贝存在的机制 (HSA 210产生DS的表型。除了精神发育迟滞 和轻微的变形特征，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改变 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。爱泼斯坦博士的团队使用的方法是基于 前提是可以将相关的特定组件 三体表型导致基因或成套基因表达增加 存在于HSA 21上的基因。爱泼斯坦博士此前曾率先提出了重要的 16三体(TS16)小鼠作为DS动物模型的研究 部分TS16模型是最近由其他人开发的。 在这项建议中，一系列方法来绘制两者的表型图谱 提出了部分的和完全的TS16。这些方法都是减法。 在本质上，它们最初是基于对变化的分析 通过端粒插入或辐射产生的三体区域 子代将根据哪些表型特征进行评估 全部或部分TS16作为特定区域的额外副本消失 染色体不再存在。这样确定的地区将是 进一步分析以确定潜在的候选基因，以及真正的作用 在三体中产生表型变化的这些区域和基因 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制造老鼠 16号染色体进行性截断的TS16胚胎干细胞 (MMU)165)，并分析表型(免疫学、造血学、中枢 从这些细胞衍生的部分TS动物的神经系统)。他和 同事们将进一步创造和鉴定TS16胚胎和胎儿 (来自具有完整和截短16s染色体的干细胞系) 关于整体形态发生、生存能力和基因表达 中枢神经系统神经元的发育，对免疫和 造血系统，以及心脏形态发生。

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.