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蛋白控制能量代谢、抗压力和寿命。在哺乳动物中，它们的功能似乎是特定的。FoxO 1是胰腺β细胞中最丰富的FoxO家族成员，它通过在餐后释放胰岛素来充当营养传感器。胰岛素，反过来，处理整个有机体的能量稳态。我们之前提供的证据表明FoxO 1在维持β细胞功能和质量方面起着关键作用。我们认为FoxO 1代表了一个潜在的中继节点，它调节胰腺β细胞的功能，以响应细胞的营养和激素状态。我们希望通过以下方式推进这项工作：1）研究FoxO 1对β细胞中各种环境因素（生长因子，产热营养素，细胞因子，氧化应激）的调节; 2）研究FoxO 1在β细胞中激活的生理后果。我们的研究计划将有助于阐明FoxO 1的复杂调控，并应推进我们对β细胞功能的分子机制的认识。

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.