Plasticity of Renewable Epithelia in the Mammalian Small Intestine

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.