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

在过去的几年中，越来越清楚的是，肠上皮细胞具有显著的动态适应环境变化的能力，例如微生物群的改变，以响应炎症，损伤或能量供应和需求的变化。这种可塑性被称为上皮重塑，其特征在于肠上皮结构和功能的协调重塑，以适当地响应变化的环境输入并最终恢复稳态。特别是，肠道可塑性对维持整个生物体的能量平衡的至关重要性已被强调，但控制肠上皮营养重塑的分子机制和转录介质仍不完全确定。另一个尚未详细研究的方面是炎症对肠上皮细胞和营养摄取的影响。最近，我们和其他人确定了c-Maf作为一种新的主转录调节因子的小肠（SI）上皮细胞，关键控制肠上皮细胞的分化和功能，特别是他们的能力，感觉和吸收营养。基于这项工作，我们假设，c-Maf也发挥了关键作用，在SI重塑过程的特点是（暂时）的变化，肠道营养吸收能力。因此，在这个项目中，我们的目标是定义如何c-Maf依赖性的营养适应的SI不同的代谢挑战（如产妇哺乳和SI炎症）的特点是在细胞和分子水平上，以及它如何决定主机的能量状态和功能。此外，我们试图确定潜在的分子机制，c-Maf控制肠上皮细胞和特定的环境信号，调节其表达。最后，我们的工作的翻译相关性将通过研究c-Maf的表达和功能，在人类肠上皮细胞从健康和发炎SI组织。总之，这项研究将使我们能够明确定义控制SI上皮营养重塑的分子回路，包括与肠道炎症相关的病理适应。预期的结果将提供一个前所未有的资源SI上皮重塑，并进行新的影响，调节肠道的吸收能力。

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.