The present PGA proposes a novel and powerful approach to dissect multigenic traits through the development of panels of chromosomal substitution strains of rats (consomic rat panels). In a panel of consomic rats, a single chromosome is replaced one at a time, so that the contribution of genes on each chromosome can be assessed by phenotyping the consomic strain for the traits of interest. Consomic rat panels enable one to assess the contribution of genes specific to that chromosome by reducing the number of QTL differences in each test and providing inbred strains with a uniform genetic background. The present PGA is therefore designed to develop, phenotype, and distribute 88 consomic strains in the form of reciprocal chromosomal substitutions. The program is built upon the existing strengths in physiology, genomics, and bioinformatics which exist within the institution. These strengths will enable the investigators to link biological functions of heart, lung, and blood systems to genomic data, development a renewable national resource for investigators to study the impact of multiple disease genes on systems biology, and provide basic information which investigators can use to understand the impact of allelic variance and their interactions with the environment upon diseases that influence the heart, lung, and blood systems. Environmental stressors such as hypoxia, exercise, and high salt intake will be used to unmask deficiencies in normal homeostatic mechanisms and idiopathic mechanisms that contribute to disease. Towards this goal, the investigators are proposing to develop and distribute 88 strains of rats in the form of reciprocal chromosomal substitution strains (consomic) of rats in which the investigators have used 317 phenotypes to characterize heart, lung, kidney, vasculature, and blood function in response to environmental stressors (hypoxia, exercise, salt intake). The investigators will utilize comparative mapping strategies to link these traits to the genomes of the mouse and human. This PGA will build upon the existing infrastructure and programmatic experience in physiological genomics and bioinformatics, to increase an understanding of the genetic basis of fundamental mechanistic pathways of the heart, lung, kidney, blood and vasculature responses to stress. The dissemination of these data and resources to a large number of investigators will provide a valuable new tool to allow the translation of genes to function and disease.
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