TCF7L2在胰高糖素受体单抗诱导胰岛β细胞再生中的作用及机制研究

胰岛β细胞体内再生对糖尿病尤其是1型糖尿病（T1D）治疗具有重要意义。本课题组前期研究表明，胰高糖素受体（GCGR）单抗可在体内诱导胰岛α细胞向β细胞转分化，增加功能性β细胞数量。预实验结果显示GCGR单抗干预可在体内、体外多个体系中上调Wnt信号通路关键效应因子TCF7L2表达，并在小鼠胰岛α细胞系中促进β-catenin入核。据此推测GCGR单抗可上调胰岛α细胞TCF7L2表达，并可参与激活Wnt通路，进而诱导胰岛α细胞向β细胞转分化，促进β细胞再生。本项目拟在两种T1D小鼠中观察GCGR单抗干预对Wnt通路关键分子表达变化的影响，在组织特异性Tcf7l2敲除小鼠中明确该基因在单抗诱导的胰岛β细胞再生中的作用，在原代胰岛、胰岛α细胞系中深入探讨TCF7L2介导GCGR单抗诱导胰岛β细胞再生的分子机制。本研究有助于阐明胰岛β细胞再生的新机制，为推动糖尿病细胞替代疗法的临床转化提供新思路。

Pancreatic β cell regeneration in vivo is of significance in diabetes especially type 1 diabetes(T1D) treatment. Previous study of our group shows that, glucagon receptor monoclonal antibody(GCGR mAb) could induce pancreatic α cell to transdifferentiate into β cell, increase functional pancreatic β-cell number. Our pilot experimental results demonstrate that GCGR mAb intervention upregulating protein or mRNA expression of the key Wnt pathway effector TCF7L2 both in vivo and in vitro, and contribute to β-catenin translocation to nucleus in αTC-1.6 cells. Based on these observations, we hypothesize that GCGR mAb could upregulate TCF7L2 expression, and at least in part be involved in Wnt pathway activation, thus induce pancreatic α cell to β cell conversion, induce β cell regeneration. In this research project, we intend to detect GCGR mAb effect on key Wnt pathway in two mouse models of T1D in vivo, to clarify the role of TCF7L2 on pancreaticβ cell regeneration induced by GCGR mAb in tissue specific Tcf7l2 knockout mice. Moreover, we plan to determine the mechanism of TCF7L2 mediated transdifferentiation induced by GCGR mAb in mouse α cell in vitro and cultured mouse primary islets ex vivo. Our project, together with other recent studies, presents an alternative scenario to explain mechanism of β cell regeneration, and contributes to clinical translation of cell replacement therapy in diabetes.