RAT GENE EXPRESSION ANATOMY

本R01申请是为了支持一项名为“人类疾病啮齿动物模型的表达特征”的PGA。该应用程序的主题是“使用基因微阵列检查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学组件，并建议利用一种新的和强大的方法，通过使用大鼠的染色体替代品系来剖析多基因特征。一只共生体大鼠的全长染色体来自一个近交系(如“病原性”品系)，并插入到另一个近交系(如“抗病”品系)的背景中。因此，22条大鼠染色体(20条常染色体，X，Y)上每条染色体上的基因对心脏、血液和肺功能的贡献可以通过22个同源大鼠品系的表型和表达谱来评估。对群体大鼠的微阵列分析提供了一种前所未有的手段，将复杂的基因表达谱与病理生理途径联系起来。这些共生体菌株之间的比较将提供有价值的见解，以了解不同菌株之间的基因组途径(“聚集”的基因表达模式)，以及这些差异可能如何与动物的特定致病表型有关。能够：(L)将心脏、血液和肺系统的生物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，教研究人员如何将这些信息应用到他们自己的R01研究项目中，这为研究界提供了宝贵的资源。

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.