Defining the molecular mechanisms driving intestinal epithelial cell specification

点击翻译按钮获取中文摘要

The intestinal epithelium is a dynamic system that constantly and rapidly regenerates throughout the***organism life. This epithelium is organized in crypt and villus compartments harboring distinct cell***populations and functions. Intestinal crypts contain epithelial stem cells surrounded by differentiated***Paneth cells. These latter cells express growth-promoting and cell-protective peptides to ensure***optimal production of progenitors from the stem cells. Intestinal villi contain differentiated subtypes***of epithelial cells including enterocytes, goblet and enteroendocrine cells. Although some clues have***been collected over the past years on the nature of the molecular mechanisms that are required for***epithelial cell specification and maintenance in this particular context, the exact regulatory circuit***involved is still not well defined. This renewal of Discovery Grant intends to pursue this program of***research and proposes to integrate, over the next five years, the interactive transcriptional network***between a set of proteins including some of which we have studied over the past years. More***precisely, our proposed work will focus on the GATA4 transcription factor, for which we have***recently identified specific novel intestinal epithelial cell functions, toward its integrated***transcriptional and biological impact with the discovery of other relevant transcriptional regulators.***We also intend to take advantage of an innovative system model that we have recently optimized in***the laboratory. This biological system consists of mini epithelial guts growing ex vivo that perfectly***recapitulate proliferation and cytodifferentiation of the intestinal epithelium. This research program***will aim to define the nature of GATA4 protein complexes susceptible to regulate the intestinal***epithelial transcriptome in stem and differentiated cells and to define the global intestinal epithelial***genetic targets of GATA4 in combination to most relevant identified interacting transcription***regulator(s). It is our hope that these strategies will provide crucial information on the nature of the***epithelial cell specific transcriptional interactome(s) in both epithelial stem and differentiated cells.***This will allow a better understanding of the nature of regulators important for intestinal epithelial cell***specification and perhaps provide novel long-term targeting strategies to alternatively produce***unique culture sets of enriched and specific subtypes of intestinal epithelial cells, models that still***await to be optimized.