Molecular mechanisms of intestinal epithelial gene transcription

肠上皮是一个高度动态的更新系统，组织在隐窝中，由增殖细胞和绒毛组成的分化细胞。 位于隐窝底部的干细胞不断产生前体细胞，这些前体细胞经历一系列分子变化，最终导致增殖停滞和分化。 虽然在过去的几年里已经收集了一些线索的性质的分子机制，所需的诱导细胞分化在这种特定的情况下，涉及到维持肠上皮细胞增殖，这是需要不断更新的上皮细胞的调节电路仍然是不明确的。 我们的研究进展导致了一个特定的基因调控（核共受体阻遏物）的鉴定，作为维持培养中的肠上皮细胞增殖的关键。 色素上皮衍生因子基因，一种在许多不同细胞系统中有效的细胞增殖抑制剂，被鉴定为被核辅受体阻遏物下调。 本研究的主要目的是进一步阐明核辅受体阻遏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，将产生遗传修饰的小鼠模型，其中核共受体阻遏物的表达将在肠上皮内特异性受损。 这些方法应该突出这种调节剂在正常肠上皮生理学中的确切作用，并从长远来看，有助于开发用于肠上皮失调功能的新型治疗工具。

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.