家族性结直肠息肉病是常见的遗传病，是由APC基因突变诱导Wnt/β-catenin通路激活而发病，目前缺乏有效的治疗药物。肠道干细胞与息肉的发病密切相关，G蛋白偶联受体182(GPR182)表达于肠道干细胞的表面，参与调控干细胞的功能及息肉的发生。项目组前期研究中首次发现IGFBP5是孤儿受体GPR182的结合配体，可下调其下游ERK通路活化水平，IGFBP5多肽可以显著抑制小鼠结直肠息肉的生长。由此我们推测在肠道内IGFBP5可以与肠道干细胞表面的GPR182结合，调控下游MAPK/ERK信号通路，影响Wnt/β-catenin通路的活化，从而调控结直肠息肉的发生进展。本项目拟从临床标本、分子水平、离体类器官和干细胞培养以及动物模型等多个方面，证实IGFBP5作为配体可以结合GPR182，探讨两者结合在结直肠干细胞功能调控及息肉发病中的作用机制，并为结直肠息肉治疗提供策略。

Familial polyposis coli is a common hereditary disease of colon, and is induced by genetic alterations of APC and downstream activation of Wnt/β-catenin. There is lack of therapeutic drugs for this disease. Intestinal stem cells are associated with pathogenesis of colonic polyps. It is reported that GPR182 is expressed on intestinal stem cells, and regulates the phenotype of stem cells and development of polyps. Our preliminary data showed that IGFBP5 represented as a novel ligand for the orphan receptor GPR182 and led to inactivation of downstream ERK signaling pathway. In genetic engineering mice with spontaneous colonic polyps, IGFBP5 peptide remarkably inhibited the growth of polyps. Based above, we speculate that IGFBP5 could regulate the phenotype of intestinal stem cells via binding to GPR182. This further lead to the interaction of MAPK/ERK and Wnt/β-catenin signaling pathway, which has a significant effect on the pathogenesis of colonic polyps. Based on the clinical samples, in vitro experiments and in vivo animal models, this project for the first time propose that IGFBP5 is a potential ligand for GPR182 and aims to explore the effect of IGFBP5/GPR182 on growth of colonic polyps. The implementation of this work could be helpful in further understanding of relationship between stem cells and formation of polyps, and in developing new therapeutic strategies for familial polyposis coli.