Grant: Discovery Grants Program - Individual

FoxO proteins are conserved in evolution from worms to mammals. The high conservation of the FoxO proteins buttresses their importance in several biological processes. In worms and flies, FoxO proteins control energy metabolism, resistance to stress and lifespan. In mammals, their function seems to be context-specific. FoxO1 is the most abundant FoxO family member in pancreatic beta-cells, which act as nutrient sensors by releasing insulin after a meal. Insulin, in turn, handles energy homeostasis for the whole organism. We previously provided evidence that FoxO1 plays a pivotal role in the maintenance of beta-cell function and mass. We propose that FoxO1 represents a potential relay node that regulates pancreatic beta-cell function in response to the nutritional and hormonal status of the cell. We wish to carry this work forward by 1) studying the regulation of FoxO1 in response to various environmental cues (growth factors, calorigenic nutrients, cytokines, oxidative stresses) in beta-cells and 2) investigating the physiological consequences of FoxO1 activation in beta-cells. Our research program will help elucidating the complex regulation of FoxO1 and should advance our knowledge of the molecular mechanisms governing beta-cell function.