BRIDGING GENES AND HEART DISEASE IN DOWNS SYNDROME

唐氏综合征（Down syndrome，DS）是先天性心脏病（Congenital Heart Disease，CHD）的主要病因之一，其发病机制与先天性心脏病（Congenital Heart Disease，CHD）的发生、发展和预后密切相关。 虽然胚胎学过程的基础垫形态优美的描述，导致基因缺陷的信号通路在很大程度上是未知的。 本提案中描述的研究的最终目标是定义导致DS-CHD的基因，定义其在垫形态发生中的作用，并提供改变其表达的模型。 该小组先前的工作已经基于人类和小鼠模型定义了DS-CHD区域，并产生了序列就绪的重叠群，其中300 kb的完成序列和1/1999的剩余序列，以及21号染色体上4 Mb候选区域中30个cDNA的转录图谱，以及可能候选区域的测序和表征。DS-CAM。 人和小鼠DS CAM克隆的分析揭示了具有10个Ig 2和6个纤连蛋白结构域以及细胞外和跨膜形式的IG超家族的高度保守的新型细胞粘附分子（CAM）。在内皮细胞垫、神经元、神经嵴和其他上皮诱导位点、已知心源性转录因子（Mef 2）的启动子位点中的表达，联合收割机与其具有小DS-CHD区域的图谱位置相结合，使DS Cam成为可能的候选者。 并非所有16号部分三体的小鼠模型（包括DS-CHD区域）都会发生心脏病。 为了阐明DS-CAM在DS-CHD中的作用，（心肌、内皮细胞、神经嵴），DS-CAM隔室特异性过表达的小鼠模型（心肌、内膜、神经嵴），将产生DS-CAM隔室特异性过表达和表达缺乏的小鼠模型，以及用于解决21号染色体基因对胶原VIa 1/VIa 2的可能贡献的模型。a2位于MMU 10上。 我们提出了四个目标; I和II缩小区域并检查人类表达; III-V（与UCSD小鼠核心和项目1合作）使用小鼠模型来测试DS-CAM是DS-CHD基因的假设，VI定义了DS-CHD区域中的其余基因。 通过确定DS-CAM及其调控和相互作用分子的作用，这项工作将提供孤立的AVSD，VSD，ASD和PS以及其他形式的单基因CHD的候选原因。 了解DS CAM将有助于深入了解正常EC形态发生及其发育不良的途径，这些途径导致大多数因先天性异常而死亡。

Down syndrome (DS) is a major cause of congenital heart disease (CHD), of which most is related to defective morphogenesis of the endocardial cushions ( EC). Although the embryologic processes underlying cushion morphogenesis are elegantly described, the signalling pathways that lead from genes to defects are largely unknown. The ultimate goal of the research described in this proposal is to define the gen(s) responsible for DS-CHD, to define its role in cushion morphogenesis and to provide models in which to modify its expression. Previous work by this group has defined a DS-CHD region based on human and mouse models and has generated a sequence ready contig, with 300 kb of finished sequence and the remainder by 1/1999, and transcriptional map of 30 cDNAs in the 4 Mb candidate region on chromosome 21, as well as sequencing and characterization of a likely candidate., DS-CAM. Analysis of the human and mouse DS CAM clones reveal a highly conserved novel class of cell adhesion molecules (CAM) of the Ig superfamily with ten Ig2 and six fibronectin domains and both extracellular and transmembrane forms. Expression in the endocardial cushions, neurons, neural crest and other sites of epithelial induction, promoter sites for known cardiogenic transcription factors (Mef2), combine with its map position with a small DS-CHD region, to make DS Cam a likely candidate. Not all mouse models of partial trisomy 16 including the DS-CHD region develop heart disease. To elucidate the role of DS-CAM in DS-CHD, the role of compartment specific expression (myocardium, endocardium, neural crest), mouse models of DS-CAM compartment specific over-expression (myocardium, endocardium, neural crest), mouse models of DS-CAM compartment specific over-expression and lack of expression will be generated as will models to address the possible contribution of the chromosome 21 gene for collagen VIa1/a2 located on MMU 10. We propose 4 aims; I and II narrow the region and examine human expression; III-V (in collaboration with the UCSD Mouse Core and Project 1) use mouse models to test the hypothesis that DS-CAM is the gene for DS-CHD, and VI defines the remainder of genes in the DS-CHD region. By defining the role of DS-CAM and its regulatory and interacting molecules, this work will provide the candidate causes for isolated AVSD, VSD, ASD and PS as well as other forms of monogenic CHD. Understanding DS CAM will provide insight into pathways on normal EC morphogenesis and their maldevelopment that cause the majority of deaths due to congenital anomalies.