GMRP1在调控胰岛β细胞增殖和凋亡过程中的作用及分子机制研究

Our group had cloned a gene that functionally related to proliferation/apoptosis of pancreatic β cells, and we named it Glucose Metabolism Related Protein 1 (GMRP1).Our previous work showed that GMRP1 can promote β cell proliferation and inhibit apoptosis via increasing phosphorylation of Akt and BAD; high glucose can increase GMRP1 expression in β cells. Knockdown of GMRP1 decreased high glucose-induced β cell proliferation and insulin-stimulated Akt phosphorylation. ChIP and luciferase-reporter system experiments showed that GMRP1 is a transcriptional activator of c-Myc gene; we have already established the GMRP1 knock out mouse model. Part of the work has been published (Diabetologia. 2011. 54: 852-863）。Based on these work, we are going to focus on animal models(type 2 diabetes animal model, GMRP1 knockout mouse model and isletβcell-specific GMRP1 knockout mouse model) and cell culture experiments, try to understand the molecular mechanism of glucose/insulin-GMRP1-Akt pathway and glucose-GMRP1-c-Myc pathway in regulating proliferation/apoptosis of pancreatic β cells, to provide new insight intoβcell research field.

课题组克隆了一个与胰岛β细胞增殖或凋亡有关的基因：GMRP1，前期的研究显示，GMRP1通过增加Akt和BAD的磷酸化，促进胰岛β细胞增殖，抑制其凋亡；高糖能够增加β细胞GMRP1表达，而抑制GMRP1的表达后，高糖促β细胞增殖明显减弱，胰岛素刺激的Akt磷酸化也明显下降；ChIP和荧光素酶报告系统研究发现，GMRP1是c-Myc基因的转录激活因子。前期部分研究结果已发表（Diabetologia. 2011. 54: 852-863.）。基于前期研究结果，课题组提出可能存在"葡萄糖/胰岛素-GMRP1-Akt"和"葡萄糖-GMRP1-c-Myc"信号通路调节胰岛β细胞增殖或凋亡过程，课题组将在细胞、糖尿病动物模型以及GMRP1基因整体剔除及胰岛β细胞特异性剔除小鼠模型等层面进行验证。

本课题组克隆了一个与胰岛β细胞增殖或凋亡有关的基因：GMRP1。课题组提出可能存在"葡萄糖/胰岛素-GMRP1-Akt"和"葡萄糖-GMRP1-c-Myc"信号通路调节胰岛β细胞增殖或凋亡过程，课题组在细胞、糖尿病动物模型以及GMRP1基因整体剔除及胰岛β细胞特异性剔除小鼠模型等层面对此信号通路进行了验证。课题组体外实验研究显示，GMRP1通过增加Akt和BAD的磷酸化，促进胰岛β细胞增殖，抑制其凋亡；高糖能够增加β细胞GMRP1表达，而抑制GMRP1的表达后，高糖促β细胞增殖明显减弱，胰岛素刺激的Akt磷酸化也明显下降；在2型糖尿病模型db/db鼠的研究也证实GMRP1在胰岛β细胞凋亡过程中发挥的作用。课题组选取8周龄GMRP1基因剔除小鼠(GMRP-/-小鼠) 和野生C57小鼠进行高脂饮食喂养，基线以及12周高脂饮食喂养后葡萄糖耐量试验均未发现显著差异。实验结果提示可能需要进行胰岛特异性敲除GMRP1以进一步研究其功能。