Diabetes, and the complications of diabetes, are the result of complex genetic and environmental interactions. In the present cycle of the AMDCC, we have sought to identify realistic animal models of the complications of diabetes by characterizing naturally occurring variations among inbred strains of mice that impact diabetes, insulin resistance and athersclerosis. Among the most promising models is the classic BKS.db mouse. BKS.db consists of a combination of alleles derived from inbred strain DBA on the background of strain C57BL/6, along with a null mutation of the leptin recepter gene db. During the present AMDCC cycle we identified all of the regions of BKS that are derived from DBA using very high density SNP mapping. These regions are scattered throughout the genome, and it is clear that multiple DBA alleles are required for the development of diabetes and its complications. We then identified two strong candidates for the DBA alleles required for diabetes: 5-lipoxygenase (5LO) and lipin, both of which are dramatically reduced in activity in BKS as compared to C57BL/6. In this application we will extend the investigations of 5LO, lipin and other genes predisposing to diabetes and its complications in BKS.db. We will also introduce the apolipoprotein E (Apo E) null mutation onto BKS to produce a model for diabetes - induced athersclerosis. To facilitate the genetic dissection of this model we have produced a whole genome set of congenic strains in which regions of DBA have been introgressed on the background of C57BL/6. Our analyses will incorporate state of the art physiologic and bioinformatic approaches and will integrate an expression quantitative trait locus (eQTL) database that we have developed over the past several years.
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