血清类粘蛋白1样蛋白3（orosomucoid 1-like protein 3，ORMDL3)作为内质网上的跨膜蛋白与内质网应激和未折叠蛋白反应有关，最近研究发现ORMLD3也是1型糖尿病相关基因。我们在前期工作中证实1型糖尿病儿童外周血淋巴细胞中ORMDL3呈低表达。进一步在胰岛β细胞中研究发现未折叠蛋白反应相关分子ORMDL3-ATF6调节轴能促进胰岛β细胞增殖。本项目拟在前期细胞实验的基础上，进一步在1型糖尿病动物模型中验证ORMDL3-ATF6在胰岛β细胞增殖中的作用。同时重点阐明ORMDL3调控胰岛细胞增殖的分子机制：确认ORMDL3通过ATF6促进胰岛细胞增殖；解析ORMDL3和ATF6间的具体调控机制及作用靶点；基因芯片筛选、蛋白验证和信号通路抑制剂干预等方法明确ATF6促胰岛β细胞增殖的下游效应途径及靶分子。所获得的研究成果将为1型糖尿病的临床防治提供新的靶点。

The ORMDL3 (orosomucoid 1-like protein 3) gene, coding for the ER-resident transmembrane protein ORMDL3, has been associated to type 1 diabetes. We analyzed the levels of ORMDL3 mRNA in peripheral blood leukocytes of normal subjects and type 1 diabetes children by RT–qPCR, and observed decreased expression of ORMDL3 in type 1 diabetes patients compared with controls. The advanced cell experiments identified ORMDL3-ATF6 as the unfolded protein response (UPR) pathway related factors induced β cell proliferation. To investigate the role of ORMDL3 and ATF6 in regulating islet beta cell function in vivo, type 1 diabetes mice will be used. We will finally focus on the potential mechanisms underlying ATF6 for mediation of β-cell proliferation: Gene chip, Western Blot, molecular inhibitor will be used to find the downstream pathway and targets of ATF6, in addition, the signal pathway between ORMDL3 and ATF6 will be identified. These studies will provide evidence for the target therapy of type 1 diabetes.