Translational Medicine and Therapeutics Programme at the University of Cambridge: 'Activating Akt mutations and metabolism: translational and therapeutic opportunities.' (360G-Wellcome-099377_Z_12_Z)

To elucidate the mechanisms by which the AKT2-E17K mutation affects the regulation of the downstream substrates involved in glucose and lipid metabolism in vitro approaches including western blotting, immunoprecipitation, quantitative PCR and confocal microscopy will be used. Complementary studies with AKT inhibitors will be performed and their effects on the above outcomes will be assessed. Transgenic mouse models of the Akt2-E17K and Akt1-E17K mutations have been obtained and detailed phenotyping of these mice will provide in vivo insights into the consequences of the E17K mutation as well as reveal important insights into the isoform specific functions of these enzymes. In addition, these mice will be used for pre-clinical studies investigating the clinical efficacy of compounds that impact upon AKT signalling. Collectively, the data collected from these studies will inform future clinical studies investigating the efficacy of AKT inhibitors in disease states characterised by hyperinsulinism.