RAT GENE EXPRESSION ANATOMY

本R 01申请是为了支持题为“人类疾病啮齿动物模型的表达谱分析”的PGA而提交的。申请的主题是“使用cDNA微阵列检测人类疾病啮齿动物模型中的基因/环境相互作用”，以将表型与基因型联系起来。为了支持这一应用，我们将建立一个大鼠基因表达解剖组件，并建议利用一种新的和强大的方法，通过使用大鼠（consomic大鼠）的染色体替代品系来解剖多基因性状。同源体大鼠具有来自一个近交系（例如“患病致病”系）的全长染色体，其渗入到另一个近交系（例如“抗性”系）的背景中。因此，驻留在22条大鼠染色体（20条常染色体，X，Y）中的每一条上的基因对心脏、血液和肺功能的贡献可以通过对一组22个染色体组大鼠品系进行表型分析和表达谱分析来评估。基因芯片分析的consomic大鼠提供了一个前所未有的手段，连接复杂的基因表达谱的病理生理途径。consomic菌株之间的比较将提供有价值的见解基因组途径（“集群”基因表达模式），菌株之间的差异，以及这些差异如何可能连接到一个特定的致病性表型的动物。能够：（l）将心脏、血液和肺系统的生物学功能与基因组表达数据联系起来，（2）开发一个国家数据库，作为存档表达数据的资源，以及（3）提供一个程序，教导研究人员如何将这些信息应用于他们自己的R 01研究程序，为研究界提供宝贵的资源。

This R01 application is submitted in support of a PGA entitled "Expression Profiling of Rodent Models of Human Disease." The theme of the application is "Examining Gene/Environment Interactions in Rodent Models of Human Disease Using cDNA Microarrays" to link phenotype to genotype. In support of that application, we will establish a Rat Gene Expression Anatomy Component and propose to take advantage of a novel and powerful approach that dissects multigenic traits through the use of chromosomal substitution strains of rats (consomic rats). A consomic rat has a full-length chromosome from one inbred strain (e.g. "diseased pathogenic" strain) introgressed onto the background of another inbred strain (e.g. "resistant" strain). Hence, the contribution of genes residing on each of the 22 rat chromosomes (20 autosomes, X, Y) to heart, blood and lung functions can be assessed by phenotyping and expression profiling a panel of 22 consomic rat strains. Microarray analysis of consomic rats offer an unprecedented means to link complex gene expression profiles to pathophysiological pathways. Comparisons between the consomic strains will provide valuable insights into the genomic pathways ("clustered" gene expression patterns) that differ between strains and how these differences might be connected to a particular pathogenic phenotype of the animal. The ability to: (l) link biological functions of the heart, blood and lung systems to genomic expression data, (2) develop a national database as a resource that archives the expression data, and (3) provide a program that teaches researchers how to apply this information to their own R01 research programs provide an invaluable resource to the research community.