The Collaborative Cross Project on Obesity and Diabetes

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DESCRIPTION (provided by applicant): Genetic studies of complex diseases like obesity and diabetes have so far not succeeded in explaining the large genetic contribution of heritability to these disorders. In humans, the studies are compromised by limited phenotyping and environmental variation. In mice, intercross studies are limited by poor mapping resolution and the lack of biological replication. The Collaborative Cross is a large community resource under development that will generate ~300 recombinant inbred strains derived from eight founder strains. The founder strains together account for ~90% of all the genetic diversity of all the inbred mouse strains, which it is widely believed, carry about as much genetic variability as the human population. The strains will be fully genotyped and will carry enough recombinations to afford high-resolution genetic mapping. We plan to carry out detailed phenotyping of these strains on high-fat diets, bringing together physiological phenotyping (e.g. glucose tolerance, lipid biochemistry) with phenotypes derived from the application of various "-omics" technologies (e.g. transcriptomics, metabolomics). For the first time, we plan to genetically map flux measurements; i.e. the true rates of synthesis of proteins, fatty acids, cholesterol, and glucose. This study is a pilot project on the eight parental strains ofthe Collaborative Cross. Our aim is to ascertain the range of variability of the phenotypes will measure so that we can justify a larger study of the recombinant inbred strains. We have assembled an experienced team with complementary expertise; 1) Alan Attie (University of Wisconsin; mouse genetics & genomics, lipid metabolism); 2) Chris Newgard (Duke University; metabolomics); 3) Gary Churchill (The Jackson Laboratory; conceived and developed the Collaborative Cross, statistical methods for the investigation of complex disease-related traits in the mouse); and 4) Henri Brunengraber (Case Western Reserve University; stable isotope technology (GC-MS and NMR) to measure changes in metabolic flux associated with chronic diseases).