Molecular regulation of intestinal epithelial cell (IEC) differentiation and function – A novel role for the transcription factor c-Maf

在过去的几年里，越来越清楚的是，肠道上皮具有显著的能力来动态适应环境变化，如微生物区系的变化，以应对炎症、损伤或能源供需的变化。这种可塑性被称为上皮重塑，其特征是肠道上皮结构和功能的协调重塑，以适当地响应不断变化的环境输入，并最终恢复内环境平衡。特别是，肠道可塑性对于维持整个生物体的能量平衡的重要性已经被强调，然而调控肠上皮营养重构的分子机制和转录介质仍然不完全清楚。另一个尚未详细研究的方面是炎症对肠道上皮细胞和养分吸收的影响。最近，我们和其他人发现c-Maf是一种新的小肠(SI)上皮主转录调节因子，它关键地控制着肠细胞的分化和功能，特别是它们感知和吸收营养的能力。基于这项工作，我们假设c-Maf也在SI重塑过程中发挥关键作用，SI重塑过程的特征是肠道养分吸收能力的(暂时性)变化。因此，在这个项目中，我们的目标是定义依赖c-Maf的SI对不同代谢挑战(例如母体哺乳和SI炎症)的营养适应是如何在细胞和分子水平上表征的，以及它如何决定宿主的能量状态和功能。此外，我们试图确定c-Maf控制肠细胞的潜在分子机制以及调节其表达的特定环境信号。最后，我们的工作的翻译相关性将通过研究c-Maf在健康和炎症SI组织中的人肠细胞中的表达和功能来确定。总而言之，这项研究将使我们能够明确地定义管理SI上皮营养重构的分子回路，包括与肠道炎症有关的病理适应。预期的结果将提供前所未有的SI上皮重塑的资源，并为调节肠道的吸收能力带来新的含义。

Throughout the last years it has become increasingly clear that the intestinal epithelium has a remarkable capacity to dynamically adapt to environmental changes, such as alterations of the microbiota, in response to inflammation, injury or variations in energy supply and demand. This plasticity, which has been coined epithelial remodelling, is characterized by a coordinated reshaping of the intestinal epithelial structure and function to appropriately respond to changing environmental input and to eventually restore homeostasis. Especially, the critical importance of intestinal plasticity for maintaining energy balance of the whole organism has been highlighted, yet the molecular mechanisms and transcriptional mediators governing the nutritional remodelling of the intestinal epithelium have remained incompletely defined. Another aspect that has not been studied in detail yet is the impact of inflammation on intestinal epithelial cells and nutrient uptake. Recently, we and others identified c-Maf as a novel master transcriptional regulator of the small intestinal (SI) epithelium, which critically controls the differentiation and function of enterocytes, especially their capacity to sense and take up nutrients. Based on this work, we hypothesize that c-Maf also plays a key role in SI remodelling processes that are characterized by (temporary) changes in the intestinal nutrient uptake capacity. Thus, in this project, we aim to define how c-Maf-dependent nutritional adaption of the SI to different metabolic challenges (e.g. maternal lactation and SI inflammation) is characterized on the cellular and molecular level and how it determines host energy status and function. Furthermore, we seek to identify the underlying molecular mechanisms by which c-Maf controls enterocytes and the specific environmental signals that modulate its expression. Finally, the translational relevance of our work will be determined by investigating c-Maf expression and function in human enterocytes from healthy and inflamed SI tissue. In sum, this study will allow us to specifically define the molecular circuits that govern the nutritional remodelling of the SI epithelium, including pathological adaptations that are linked to intestinal inflammation. The anticipated results will provide an unprecedented resource of SI epithelial remodelling and carry novel implications for the modulation of the absorptive capacity of the gut.