Plasticity of Renewable Epithelia in the Mammalian Small Intestine

对于大多数细胞来说，调节基因表达的信号通常来自内部信号。然而，肠上皮细胞独特地暴露于消化的食物中，需要对饮食或营养可用性的变化做出反应。该奖项将支持研究肠上皮细胞适应性特征的创新实验方法，从而极大地扩展我们对哺乳动物上皮生物学和肠道调节的理解。首席研究员将把这个研究项目与教育活动结合起来，包括研究生和博士后研究员，以及通过以前与他们的高中和大学建立联系招募的市中心学生。这些研究的结果将通过同行评议的期刊出版物以及通过在区域和国家科学会议上的介绍来分发。以具有广泛代表性的果糖转运体GLUT5对其底物饮食水平的反应为实验模型，第一个目的是验证肠道干细胞（ISCs）及其后代对饮食线索具有不同适应能力的假设。它将决定ISCs以及完全分化的吸收和分泌细胞是否对果糖有感知和反应，这种反应是否可逆，以及ISCs短暂暴露于果糖所产生的分子信息是否能够被记忆并传递给分化的后代。第二个目标将验证果糖代谢通过细胞能量传感器AMP激酶调节GLUT5表达的假设，并评估营养代谢对果糖反应细胞适应性反应的贡献。由于营养物质调节其自身的转运蛋白，本研究对GLUT5的调节提供了对各种肠细胞类型的转运蛋白如何响应其底物的管腔浓度变化的广泛理解。

For most cells, the signals regulating gene expression typically arise from internal cues. Intestinal epithelial cells however are uniquely exposed to digested food and need to respond to changes in diet or nutrient availability. This award will support innovative experimental approaches to investigate the adaptive characteristics of intestinal epithelial cells, thereby dramatically expanding our understanding of mammalian epithelial biology and intestinal regulation. The principal investigator will integrate this research program with educational activities involving graduate students and postdoctoral fellows, as well as inner city students recruited via previously established links with their high schools and colleges. Results from the studies will be distributed through peer-reviewed journal publications, and through presentations at regional and national scientific meetings.Using the broadly representative response of the fructose transporter GLUT5 to dietary levels of its substrate as experimental model, the first aim tests the hypothesis that intestinal stem cells (ISCs) and their progenies have different capacities to adapt to dietary cues. It will determine whether ISCs as well as fully differentiated absorptive and secretory cells perceive and respond to fructose, whether the response is reversible, and whether molecular information arising from transient exposure of ISCs to fructose can be memorized and transmitted to differentiating progenies. The second aim will test the hypothesis that fructose metabolism regulates GLUT5 expression via the cellular energy sensor AMP kinase and assess the contribution of nutrient metabolism to the adaptive response of fructose-responsive cells. Because nutrients regulate their own transporters, this study on GLUT5 regulation provides a broad understanding of how transporters in various intestinal cell types respond to changes in luminal concentrations of their substrates.