Defining the molecular mechanisms driving intestinal epithelial cell specification

定义驱动肠上皮细胞规范的分子机制

• 批准号: RGPIN-2017-06096
• 负责人: Boudreau, François
• 金额: $ 3.64万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=712049
• 关键词: Defining; molecular; mechanisms; driving; intestinal

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.

肠上皮细胞是一个动态系统，在整个肠道内不断快速再生。 有机体生命上皮由隐窝和绒毛组成，有不同的细胞 人口和功能。肠隐窝含有上皮干细胞， 潘氏细胞。这些后一种细胞表达促进生长和细胞保护肽， 从干细胞中最佳地产生祖细胞。肠绒毛含有分化的亚型 上皮细胞包括肠上皮细胞、杯状细胞和肠内分泌细胞。尽管有些线索 在过去的几年里，人们收集了关于 上皮细胞的特化和维持在这个特定的背景下，确切的调节回路 涉及的范围还没有很好的界定。此次发现补助金的更新旨在推动这一计划， 研究并建议在未来五年内整合交互式转录网络， 包括我们过去几年研究过的一些蛋白质。更 确切地说，我们的工作将集中在GATA 4转录因子上，我们已经 最近确定了特定的新型肠上皮细胞功能， 转录和生物学的影响与其他相关的转录调节因子的发现。 我们还打算利用我们最近优化的创新系统模型， 实验室这种生物系统由离体生长的微型上皮肠组成， 重演肠上皮细胞的增殖和细胞分化。这个研究项目 目的是确定GATA 4蛋白复合物的性质， 干细胞和分化细胞中的上皮转录组，并定义整体肠上皮细胞 GATA 4的遗传靶点与最相关的已鉴定相互作用转录的组合 调节器。我们希望这些策略能够提供有关其性质的重要信息 上皮干细胞和分化细胞中的上皮细胞特异性转录相互作用物组。 这将使我们更好地了解对肠上皮细胞重要的调节因子的性质。 说明书，并可能提供新的长期靶向策略， 独特的培养集的丰富和特定亚型的肠上皮细胞，模型，仍然 有待优化。