Age-dependent beneficial effects of PI3-Kinase pathway inactivation on glucose and lipid homeostasis: Mechanisms and therapeutic potential in metabolic disease. (360G-Wellcome-093115_Z_10_Z)

Preliminary data demonstrate that inactivation of PI 3-Kinase p110alpha exerts a beneficial effect on glucose and lipid homeostasis in aged mice. We will dissect the mechanism underlying this effect. We will use constitutive or conditionally p110alpha gene-targeted mice. Muscle and adipose tissue are peripheral tissues with key roles in the regulation of glucose and lipid homeostasis. We will therefore specifically inactivate p110alpha in these tissues to assess their contribution to the phenoty pe of global p110alpha inactivation. To achieve this, we will challenge young and aged p110alpha gene-targeted mice with high-fat feeding followed by comprehensive metabolic phenotyping. In order to elucidate the molecular mechanisms underlying these effects, we will characterise signalling pathway activation and perform transcriptome analysis in insulin-sensitive tissues of these mice. We will also assess the effect of p110alpha inactivation on cellular bioenergetic capacity by studying mitoch ondrial biogenesis and function. The genetic experiments will be complemented by pharmacological inhibition and RNA interference of p110alpha expression in primary cells or established cell lines representative of insulin target cells. Our ultimate aim is to provide proof-of-principle that the p110alpha signalling pathway can be therapeutically targeted in the prevention/treatment of age-dependent obesity and type-2 diabetes and promote healthier ageing.