Defining the molecular mechanisms driving intestinal epithelial cell specification

肠上皮细胞是一个动态系统，在机体的整个生命过程中不断快速再生。这种上皮组织在隐窝和绒毛隔室窝藏不同的细胞群和功能。肠隐窝含有上皮干细胞，周围有分化的潘氏细胞。这些后一种细胞表达促进生长和细胞保护肽，以确保从干细胞中最佳地产生祖细胞。肠绒毛含有分化的上皮细胞亚型，包括肠上皮细胞、杯状细胞和肠内分泌细胞。尽管在过去的几年里已经收集到了一些线索，这些线索是关于在这种特殊情况下上皮细胞特化和维持所需的分子机制的性质，但涉及的确切调控回路仍然没有很好的定义。这次更新的发现补助金打算继续这项研究计划，并建议在未来五年内整合一组蛋白质之间的相互作用的转录网络，包括我们在过去几年中研究的一些蛋白质。更准确地说，我们的工作将集中在GATA 4转录因子上，我们最近发现了它的特异性新的肠上皮细胞功能，并将其与其他相关转录调节因子的发现结合起来，以实现其整合的转录和生物学影响。我们还打算利用我们最近在实验室优化的创新系统模型。该生物系统由离体生长的微型上皮肠组成，其完美地再现了肠上皮的增殖和细胞分化。这项研究计划旨在确定GATA 4蛋白复合物的性质，这些蛋白复合物易于调节干细胞和分化细胞中的肠上皮转录组，并确定GATA 4与最相关的相互作用转录调节因子组合的全球肠上皮遗传靶点。我们希望这些策略将提供关于上皮干细胞和分化细胞中上皮细胞特异性转录相互作用组的本质的关键信息。这将允许更好地理解对肠上皮细胞特化重要的调节因子的本质，并可能提供新的长期靶向策略，以交替地产生富集和特异性肠上皮细胞亚型的独特培养集，models模型that stillawait等待to be optimized优化.

The intestinal epithelium is a dynamic system that constantly and rapidly regenerates throughout theorganism life. This epithelium is organized in crypt and villus compartments harboring distinct cellpopulations and functions. Intestinal crypts contain epithelial stem cells surrounded by differentiatedPaneth cells. These latter cells express growth-promoting and cell-protective peptides to ensureoptimal production of progenitors from the stem cells. Intestinal villi contain differentiated subtypesof epithelial cells including enterocytes, goblet and enteroendocrine cells. Although some clues havebeen collected over the past years on the nature of the molecular mechanisms that are required forepithelial cell specification and maintenance in this particular context, the exact regulatory circuitinvolved is still not well defined. This renewal of Discovery Grant intends to pursue this program ofresearch and proposes to integrate, over the next five years, the interactive transcriptional networkbetween a set of proteins including some of which we have studied over the past years. Moreprecisely, our proposed work will focus on the GATA4 transcription factor, for which we haverecently identified specific novel intestinal epithelial cell functions, toward its integratedtranscriptional 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 inthe laboratory. This biological system consists of mini epithelial guts growing ex vivo that perfectlyrecapitulate proliferation and cytodifferentiation of the intestinal epithelium. This research programwill aim to define the nature of GATA4 protein complexes susceptible to regulate the intestinalepithelial transcriptome in stem and differentiated cells and to define the global intestinal epithelialgenetic targets of GATA4 in combination to most relevant identified interacting transcriptionregulator(s). It is our hope that these strategies will provide crucial information on the nature of theepithelial 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 cellspecification and perhaps provide novel long-term targeting strategies to alternatively produceunique culture sets of enriched and specific subtypes of intestinal epithelial cells, models that stillawait to be optimized.