Genetic dissection of mechanisms linking cell dysfunction, insulin resistance & major human disease

That insulin resistance (IR) is a critical mediator of obesity-related pathologies including diabetes, atherosclerosis, fatty liver, polycystic ovaries and some cancers is established. However the underlying molecular mechanisms are relatively poorly understood, in part because of imprecise clinical terminology, and difficulty in discerning primary perturbations in complex disease. This proposal circumvents these problems by focussing on rare and extreme disorders of insulin action, up to 5 of which I believe to be accounted for by recently detected novel mutations affecting either the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, or cellular DNA damage response (DDR) pathways. Physiological and cellular studies of affected patients, including study of induced pluripotent stem cells and derived cell types, will seek first to establish beyond doubt the pathogenicity of the observed mutations, and then both to assess possible therapeutic strategies for those conditions and to addre ss questions about the affected pathways in common IR-related pathology. Two novel mouse models of human PIK3R1 and AKT2 defects will also be studied. Anticipated outcomes include 1. Detailed characterisation of up to 5 novel human genetic diseases 2. Therapeutically relevant insights into the role of PI3K/AKT in IR-related disease and 3. Insights into the role of abnormal DDR pathways in IR.