The primary research interest of our group is the genetic aetiology of type 2 diabetes. Type 2 diabetes is a very common late onset disease with an ever-increasing incidence and is characterised by insulin resistance and defects in insulin secretion. This disease has a strong genetic component and is likely affected by the interaction of many relatively small effect genes. Our research is aimed at identifying genes, pathways and processes underlying the susceptibility to type 2 diabetes using the mouse as a model system. This will provide new genes for testing and pathways for targeted therapeutic intervention as well as leading to a greater understanding of the genetic regulation of glucose homeostasis.
In order to provide a sensitised system for detecting mutations in other genes that lead to diabetes, we have commenced an ENU mutagenesis programme in which mice that are insulin resistant due to targeted disruption of genes such as the insulin receptor (IR) and insulin receptor substrate 1 (IRS-1), are used. We have identified 4 lines with inherited phenotypes that are in the process of being mapped. We have also analysed animals with glucose phenotypes that are produced from the ENU mutagenesis of common inbred strains without any sensitisation in order to identify dominant monogenic models. We have 5 lines that exhibit a clear inherited phenotype. Of these we have mapped two and are testing candidate genes to refine the map location.
We are also piloting a candidate gene approach using an archived ENU mutagenised DNA resource paralleled by frozen sperm in order to recover animals with mutations in genes of interest. We have recently shown that this approach works (Coghill et al., 2002) by identifying mutations in a gene and recovering mice with a phenotype from the sperm archive. Screening is being carried out using DHPLC mutation scanning technologies.
In order to understand the complex genetics of diabetes we have mapped diabetes related phenotypes in crosses between selected inbred strains in order to map and clone QTLs. We have mapped loci in an F2 intercross between C3H and C57BL/6 and are breeding lines to generate congenics carrying these individual loci.