The theme of this application is examining gene/environment interactions in rodent models of human disease using cDNA microarrays to link phenotype to genotype. Disease phenotypes arise from complex interactions of organisms with their environments. While the investigators have a long history of associating genes and gene defects with a large array of disease phenotypes, a growing body of data suggests that many disease phenotypes arise from the interactions of genes with their environments, including the genetic background in which the genes are expressed. The goal is to begin an exploration of these interactions using rodent models of human disease and cDNA microarray assays to elucidate patterns of gene expression. This PGA brings together biologists, statisticians, computer scientists, engineers, and physicists who are will lend their expertise to the achievement of the common goals. The proposal builds on existing expertise at TIGR in the analysis of gene expression using cDNA microarrays, the mouse mutagenesis and phenotyping programs that have been developed by The Jackson Laboratories and their collaborators at Penn, Duke, and Boston Universities, and the efforts in rat genomics underway at the Medical College of Wisconsin, including the generation of phenotypically characterized consomic and congenic rat strains. Linking these programs are coordinated efforts in informatics that will both facilitate data exchange between consortium members and will make that data easily accessible to the wider research community. Underlying this is a commitment to continuing to develop and improve the reagents and assays to provide a firm statistical basis for any inferences that the assays provide. Finally, the investigators maintain a commitment to community service and will provide reagents, software, and data generated as part of this PGA to the wider research community. The investigators will develop high-density mouse and rat cDNA microarrays and use these to characterize gene expression in mouse and rat models of heart, lung, and blood diseases as well as sleep disorders. The rodent models to be surveyed will be ascertained by measuring phenotypic response of congenic, consomic, and mutagenized animals to environmental challenges known to elicit responses relevant to these diseases. Gene expression data will be integrated with genotype and phenotype data and analyzed to begin to develop a more complete understanding of the mechanistic basis for these diseases as well as the modifying and mitigating factors contributed by the environment.
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| Cook, Donald N; Whitehead, Gregory S; Burch, Lauranell H et al. (2006) Spontaneous mutations in recombinant inbred mice: mutant toll-like receptor 4 (Tlr4) in BXD29 mice. Genetics 172:1751-5 |
| Schwartz, David A; Cook, Donald N (2005) Polymorphisms of the Toll-like receptors and human disease. Clin Infect Dis 41 Suppl 7:S403-7 |
| Brass, David M; Savov, Jordan D; Whitehead, Gregory S et al. (2004) LPS binding protein is important in the airway response to inhaled endotoxin. J Allergy Clin Immunol 114:586-92 |
| Savov, Jordan D; Whitehead, Gregory S; Wang, Jianme et al. (2004) Ozone-induced acute pulmonary injury in inbred mouse strains. Am J Respir Cell Mol Biol 31:69-77 |
| Hollingsworth 2nd, John W; Cook, Donald N; Brass, David M et al. (2004) The role of Toll-like receptor 4 in environmental airway injury in mice. Am J Respir Crit Care Med 170:126-32 |
| Cook, Donald N; Pisetsky, David S; Schwartz, David A (2004) Toll-like receptors in the pathogenesis of human disease. Nat Immunol 5:975-9 |
| Cook, Donald N; Wang, Shuibang; Wang, Yonghong et al. (2004) Genetic regulation of endotoxin-induced airway disease. Genomics 83:961-9 |
| Cook, Donald N; Wang, Shuibang; Howles, Gabriel P et al. (2003) The genetics of innate immunity in the lung. Chest 123:369S |
| Whitehead, Gregory S; Walker, Julia K L; Berman, Katherine G et al. (2003) Allergen-induced airway disease is mouse strain dependent. Am J Physiol Lung Cell Mol Physiol 285:L32-42 |
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