CHROMOSOME 21 GENES--DISEASE AND HOLOPROSENCEPHALY

21 号染色体基因——疾病与前脑无裂畸形

• 批准号: 3778958
• 负责人: JULIE R KORENBERG
• 金额: --
• 依托单位: ELEANOR ROOSEVELT INST FOR CANCER RES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3778958
• 关键词: Downs syndrome; artificial chromosomes; brain; chromosomes; clone cells; complementary DNA; congenital brain disorder; congenital heart disorder; developmental genetics; developmental neurobiology; embryo /fetus cell /tissue; gene deletion mutation; genetic library; genetic mapping; genetic markers; genetically modified animals; heart; human genetic material tag; in situ hybridization; kidney; laboratory mouse; liver; lung; mental retardation; nucleic acid probes; nucleic acid sequence; polymerase chain reaction; prosencephalon; pulsed field gel electrophoresis; trisomy

Down syndrome (DS) is a major cause of mental retardation and congenital heart disease affecting the welfare of more than 300,000 individuals and their families in the USA alone. In addition, DS syndrome carries an increased risk of leukemia, congenital gut disease, defects of the immune system, and an Alzheimer-like dementia. Little is known about the molecular events that cause the DS features or of the genes that determine the early embryonic stage whose program is disrupted. The ultimate goal of the research described in this proposal is to define the genes and their functions responsible for the phenotypic features of DS. The specific aims of this proposal are designed to identify the chromosome 21 genes responsible for DS congenital heart disease (DS-CHD) and for holoprosencephaly (HP) or abnormal forebrain cleavage, due to monosomy for chromosome 21 (HP-21). Molecular markers for chromosome 21 consensus regions that are likely to contain the genes for congenital heart disease and holoprosencephaly have been defined. The specific aims are: 1) To define the limits of the DS-CHD region by molecular analyses of DS-CHD cell lines, using DNA probes not yet used to analyze this region including 26 new markers mapping in this region, and by the genetic analysis of autosomal dominant endocardial cushion defect; and for 21-HP, by molecular analyses of cell lines from 21-HP deletion and 40 spontaneous HP cases with normal chromosomes; 2) To define Yeast artificial chromosomes and cosmids within these regions; 3) To define genes that map in these regions and are expressed in both the human embryo and the fetal heart (DS-CHD) or brain (21-HP). To do this, human embryonic and fetal heart and brain cDNA libraries will be constructed and genes present in the YACs and cosmids will be defined using exon amplification and hybrid selection techniques, from 21 microclones, and from cDNAs with developmental motifs; 4) To characterize DS-CHD and 21-HP cDNAs by establishing map location, DNA sequence, expression in human (normal and DS) and mouse (normal and trisomy 16) embryonic and fetal tissues, protein studies, and ultimately, transgenic mice. These studies will define genes involved in the developmental programming of the human embryonic brain and heart that map on chromosome 21 and may be in part responsible for DS congenital heart disease and mental retardation.

唐氏综合症（DS）是智力低下和先天性的主要原因 心脏病影响300,000多人的福利， 他们的家人一个人在美国。 此外，DS综合征带有 白血病，先天性肠道疾病的风险增加，免疫缺陷 系统和类似阿尔茨海默氏症的痴呆症。 关于 引起DS特征或基因的分子事件 确定该程序被破坏的早期胚胎阶段。 这 本提案中描述的研究的最终目标是定义 基因及其功能负责DS的表型特征。 该提案的具体目的旨在确定 导致DS先天性心脏病（DS-CHD）的21个染色体基因 以及由于全hp脑（HP）或异常前脑裂解，原因是 染色体21（HP-21）的单肌。 21种共识区域的分子标记物可能可能 含有先天性心脏病和全脑脑的基因具有 已定义。 具体目的是： 1）通过分子分析来定义DS-CHD区域的极限 DS-CHD细胞系，使用尚未用于分析此的DNA探针 区域，包括该地区的26个新标记映射，以及 常染色体显性心内膜垫缺损的遗传分析； 对于21-HP，通过分子分析21-HP的细胞系 缺失和40例自发的HP病例患有正常染色体； 2）在其中定义酵母人工染色体和宇宙 地区； 3）定义在这些区域中绘制的基因，并在两者中表达 人类胚胎和胎儿心脏（DS-CHD）或大脑（21-HP）。 到 这样做，人类胚胎和胎儿心脏和脑cDNA库 将构建，YAC和宇宙中存在的基因将 使用外显子扩增和混合选择来定义 技术，来自21个微钟，来自具有发育性的cDNA 图案； 4）通过建立DS-CHD和21-HP cDNA表征 地图位置，DNA序列，在人（正常和DS）中的表达和 小鼠（正常和三体性16）胚胎和胎儿组织，蛋白质 研究，最终是转基因小鼠。 这些研究将定义与发展计划有关的基因 在21号染色体上映射的人类胚胎大脑和心脏的 部分负责DS先天性心脏病和精神 迟钝。