Molecular mechanisms of intestinal epithelial gene transcription

肠上皮是组织在隐窝中的高度动态的更新系统，由增殖细胞和由分化细胞组成的绒毛组成。隐窝底部的干细胞不断地产生前体细胞，这些前体细胞经历了一系列的分子变化，最终导致增殖停止和承诺分化。尽管在过去的几年里已经收集了一些关于在这种特殊情况下诱导细胞分化所需的分子机制的性质的线索，但参与维持肠上皮细胞增殖的调节电路仍然不清楚，这是维持肠上皮细胞持续更新所必需的。我们的研究进展导致了一种特定的基因调节因子(核共受体抑制物)被确定为在培养中维持肠上皮细胞增殖的关键。在许多不同的细胞系统中，色素上皮衍生因子基因是一种有效的细胞增殖抑制因子，被发现受到核共受体抑制物的下调。这一建议的主要目的是进一步描述核共受体抑制物靶向该基因并维持肠上皮细胞增殖的确切分子机制。此外，还将产生转基因小鼠模型，在该模型中，核共受体抑制物的表达将在肠道上皮中受到特定的损害。这些方法应该突出这种调节因子在正常肠上皮生理中的确切作用，并从长远来看，有助于开发新的治疗工具来解除对肠上皮功能的调控。

The intestinal epithelium is a highly dynamic renewal system organized in crypts, that are populated by proliferative cells, and villi composed of differentiated cells. Stem cells at the bottom of the crypts constantly produce precursor cells that undergo a succession of molecular changes that utimately lead to an arrest of proliferation and a commitment to differentiate. Although some clues have been collected over the past years on the nature of the molecular mechanisms that are required for the induction of cellular differentiation in this particular context, the regulatory circuit involved into the maintenance of intestinal epithelial cell proliferation that is required for continuous renewal of this epithelium still remains poorly defined. The progress of our research has led to the identification of a specific gene regulator (nuclear co-receptor repressor) as being crucial to maintain intestinal epithelial cell proliferation in culture. The pigment-epithelial-derived-factor gene, a potent inhibitor of cellular proliferation in a number of different cell systems, was identified to be down-modulated by the nuclear co-receptor repressor. The main objective of this proposal is further characterize the exact molecular mechanims by which the nuclear co-receptor repressor can target this gene and maintain intestinal epithelial cell proliferation. In addition, genetically modified mouse models will be generated in which the expression of the nuclear co-receptor repressor will be specifically impaired within the intestinal epithelium. These approaches should highlight the exact role for this regulator into normal intestinal epithelial physiology and in long term, contribute to the development of novel therapeutic tools for deregulated fonctions of the intestinal epithelium.