成人胰腺已高度分化，其再生胰岛细胞的能力有限。我们的前期临床实践发现成年糖尿病及非糖尿病人胰腺导管具有胰岛素阳性表达的细胞，提示导管分化为胰岛样细胞的前景值得深入研究。本课题拟对分离纯化成年小鼠胰腺导管上皮细胞经siRNA下调Fbw7表达，采用诱导技术转分化为胰岛样细胞后进行形态学和功能鉴定。将功能性胰岛细胞移植入1型、2型糖尿病小鼠模型，进行术后血糖及胰岛素等代谢参数评价。同样的实验手段对人胰腺导管上皮细胞（hTERT-HPNE）进行Fbw7沉默后诱导转分化，鉴定分化胰岛样细胞的形态和生理功能特性，并进行胰岛移植后的体内代谢指标研究。本项目采用分子生物学技术，明确Fbw7调控因子对泛素化降解底物蛋白的影响，以及对特异性蛋白/基因和Notch通路关键调节因子表达的负调控作用。旨在探讨成年胰腺导管上皮细胞的分化潜能，为其转化为胰岛样细胞提供理论依据，进而为临床胰岛移植提供新的途径。

Adult pancreas has been highly differentiated, which the regenerative capability into islet cells is limited. Our preclinical observations showed that adult diabetic and non-diabetic pancreatic tissue had insulin-producing cells, suggesting the prospect of ductal cells differentiating into islet-like cells merit further study. This study intends to down-regulation of Fbw7 by siRNA on isolated adult mouse pancreatic ductal epithelial cells and to induce transdifferentiation in vitro, then identifying the morphology and function of transdifferentiated pancreatic islet-like cells. Functional islet cells are transplanted into type 1, type 2 diabetic mice, and then metabolic parameters, such as blood glucose and insulin, are evaluated. The same experimental steps are conducted in human pancreatic ductal epithelial cells (hTERT-HPNE) for transdifferentiation via Fbw7 silence. After identifying the morphological and physiological functional characteristics of differentiated islet-like cells, metabolic indexes in vivo are determined following islet transplantation. In addition, this project applies molecular biology techniques to confirm impact of Fbw7 regulatory factor on substrate protein levels during ubiquitination, as well as to investigate negative regulation of Fbw7 on expression of endocrine specific proteins/genes and critical regulator associated with Notch signaling pathway during cell differentiation. We aim to explore the physiological differentiation potential of adult ductal epithelial cells, and to provide a theoretical basis for transdifferentiation into islet-like cells, thereby offering new avenues for clinical islet transplantation.