RBP4通过JAK/STAT/Grb10信号通路调控胰岛β细胞功能及数量

项目名称： RBP4通过JAK/STAT/Grb10信号通路调控胰岛β细胞功能及数量

项目编号： No.81500589

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李羚

作者单位： 同济大学

项目金额： 18万元

中文摘要： 脂肪因子作为“脂肪-胰岛内分泌轴”的重要组成部分可直接影响胰岛β细胞功能及数量并参与2型糖尿病发生发展。本课题组前期研究发现脂肪因子RBP4可诱导胰岛细胞中Grb10（胰岛素信号通路的负调控蛋白）表达增多，后者过表达抑制胰岛素分泌。并首次发现RBP4细胞表面受体Stra6在胰岛中高表达。相关研究发现激活Stra6下游的JAK/STAT通路抑制胰岛素合成。故本研究提出RBP4通过激活JAK/STAT/Grb10信号通路来调控胰岛β细胞功能及数量的假说，拟用RBP4干预来观察胰岛素合成及分泌、胰岛β细胞增殖和凋亡的变化。在2型糖尿病动物模型中通过反义寡核苷酸技术降低RBP4浓度，在体观察胰岛β细胞分泌功能、增殖和凋亡的改变。最后利用shRNA干扰Stra6表达及药物阻抑JAK/STAT通路，探讨代谢紊乱时RBP4对功能性胰岛细胞量的网络调节机制，为预防和治疗2型糖尿病找到潜在靶点。

中文关键词： 胰岛β细胞功能；胰岛细胞量；视黄醇结合蛋白4；2型糖尿病

英文摘要： Adipokines form the important part of the ‘adipo-insular axis’, dysregulation of which contributes to β-cell failure and hence to the development of type 2 diabetes. Our previous study showed that serum retinal binding protein 4 (RBP4, an adipokine) was correlated with glucose-stimulated insulin secretion in adults with normal glucose tolerance, and RBP4 induced the expression of growth factor receptor binding protein 10, a negative regulator of insulin release and insulin signaling pathway in pancreatic β-cells. We also found that the RBP4 receptor, Stimulated by Retinoic Acid 6 (Stra6), was highly expressed in islets for the first time. Moreover, activation of JAK/STAT pathway, downstream signaling pathway of RBP4 receptor, inhibited preproinsulin gene expression. The effect of RBP4 on maintaining β-cell function and mass is still largely unknown and needs to be revealed urgently. So we infer that RBP4 may regulate β-cell function and mass by activation of JAK/STAT/Grb10 signaling pathway and inhibition of insulin signaling pathway . In the current study, we intend to treat rat islets with recombinant human RBP4 and then observe the effects of RBP4 on β-cell function, proliferation and apoptosis. Since lowering transthyretin (TTR) increases renal clearance of RBP4, we observe if lowing circulating RBP4 by decreasing TTR with antisense oligonucleotides (ASOs) can increase insulin secretion and β-cell mass in mouse model of type 2 diabetes. Furthermore, we aim to reveal the mechanisms for the effect of RBP4 on β-cell function and mass with deletion of Stra6 using shRNA and inhibition of JAK with drug. Our study will identify a potentially important new role for RBP4 in the development of β-cell failure, and find new targets for the development of antidiabetic drugs.

英文关键词： β-cell function;β-cell mass;RBP4;type 2 diabetes