The biological theme links genetic variation to biological function and dysfunction. Using a phenotype-driven approach, the investigators will identify genetic mechanisms underlying the physiology and pathophysiology of atherosclerosis, hypertension, lung, function, blood formation, thrombosis, obesity, inflammation, and sleep function. The mouse is the premier experimental organism with which to link genes to biological function, mechanisms of disease, and disease variation in humans. Mice and humans share a remarkably similar genome and get many of the same diseases. The knowledge of the mouse genome makes possible the application of extremely powerful genetic and molecular techniques to identify genes and interacting gene networks (quantitative trait loci, QTL). QTL analyses that are not possible in man can be performed in mice, allowing genetic dissection of complex human diseases. Genome sequencing has created a pressing need to generate additional mutants and apply high-throughput screening strategies to detect mutations altering functional pathways. The problems in the past have been that the spontaneous mutation rate in mice is low, and that many phenotypes are not detected in routine colony maintenance because they are not visible (e.g., hypertension, atherosclerosis). Moreover, targeted mutagenesis requires prior knowledge of gene structure. To overcome these problems and to link both QTL and single-gene mutations to gene function and to dissect the genetic variation underlying complex cardiovascular, lung, hematopoietic, and sleep dysfunction, the investigators will establish a Center for Mouse Models of Heart, Lung, Blood, and Sleep Disorders at The Jackson Laboratory. The Center will: (1) Characterize common inbred mouse strains to identify variation in heart, lung, blood, and sleep-disorder phenotypes, and locate the major QTL affecting each phenotype; (2) Perform genome-wide mutagenesis to generate new mutations, and develop alternative mutagenesis technologies; (3) Perform high-throughput screening to detect deviants in multiple phenotypic domains; (4) Develop databases to ensure that all data generated are available to the scientific community; (5) Provide training and educational programs; (6) Distribute pathogen-free mice; and (7) Establish an internal program to effectively administer and coordinate the Center's activities.
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