探讨胰岛β细胞复分化在胃绕道手术后胰岛改善中的作用

The source of β cells in adults has two hypotheses: differentiation of stem cells and β-cell self-replicating. Recent studies have shown that β cells can de-differentiate to a non-β cells (endocrine precursor cells)in diabetic individuals. Our preliminary results suggest that gastric bypass surgery has significantly improved islet structures and functions, along with decrement of the de-differentiation of islet β cells and increment of FOXO-1 expression. This application using islet β cell lineage tracing and bidirectional tracing of dedifferentiated islet β cells, set forth in the transgenic mice after gastric bypass surgery in type 2 diabetes: 1. Whether de-differentiated islet β cells can re-differentiate in vitro and in vivo? 2. Revealing the changes of FOXO-1-related major signaling molecules control the dramatic changes. This study will not only further clarify the source of β cells in adult individuals, but also can obtain the islet β cells specific gene expression profiles of various statusbe in vivo without separation islets, evaluation of re- differentiated β cells as a sourse of cell replacement therapy in diabetics, providing a new way for the treatment of type 2 diabetes.

在成熟个体中β细胞的来源存在干细胞分化和β细胞自我复制两种假说。最近研究表明，糖尿病个体中β细胞能够去分化为非β细胞（内分泌前体细胞）。我们前期的结果提示胃绕道手术后，胰岛明显改善，伴随去分化的胰岛β细胞减少，与转录因子FOXO-1显著相关。本课题通过谱系示踪胰岛β细胞和双向示踪去分化的胰岛β细胞，阐明在转基因小鼠2型糖尿病胃绕道手术后，去分化的胰岛β细胞在体内外能否复分化，同时揭示与FOXO-1相关的主要信号分子的变化。该研究不仅能进一步澄清成熟个体中β细胞的来源，同时能在不进行胰岛分离的情况下，获得活体胰岛β细胞多种状态的特异基因表达图谱，评价复分化细胞作为糖尿病β细胞替代治疗的可能性，为2型糖尿病治疗和改善胰岛失代偿提供新途径。

本课题以转基因小鼠为研究对象，着重研究了胃绕道手术后胰岛β细胞能否复分化，及其在胃绕道手术后胰岛改善中的作用，同时从系统层面研究复分化的β细胞、成熟β细胞以及从导管细胞分化来的β细胞在增殖、抗凋亡和改善糖尿病上是否有优势，β细胞在去分化和复分化的过程中的基因表达的差异，开发糖尿病相关的组学分析方法，进行了系统生物学和网络生物学分析。本项目不仅能明确去分化β细胞能否复分化，获得活体胰岛β细胞特异基因表达图谱，为改善2型糖尿病胰岛失代偿提供新途径。