Role of the forkhead transcription factor foxo1 in pancreatic beta-cell mass and function

FOXO蛋白在从蠕虫到哺乳动物的进化过程中是保守的。FoxO蛋白的高度保守性支持了它们在几个生物过程中的重要性。在蠕虫和苍蝇中，FoxO蛋白控制着能量代谢、对压力的抵抗力和寿命。在哺乳动物中，它们的功能似乎是特定于环境的。Foxo1是胰岛β细胞中含量最丰富的FoxO家族成员，它作为营养感受器在餐后释放胰岛素。反过来，胰岛素负责维持整个生物体的能量平衡。我们之前提供的证据表明，FoxO1在维持β细胞功能和质量方面发挥着关键作用。我们认为FoxO1代表了一个潜在的继发节点，它调节胰岛β细胞的功能，以响应细胞的营养和激素状态。我们希望通过1)研究FoxO1在β细胞中对各种环境信号(生长因子、生热营养物质、细胞因子、氧化应激)的调节以及2)研究FoxO1激活在β细胞中的生理后果来推进这项工作。我们的研究计划将有助于阐明FoxO1的复杂调控，并应促进我们对调控β细胞功能的分子机制的了解。

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.