Role of estrogen receptors in pancreatic beta-cell survival and insulin secretion

在糖尿病中，胰腺中产生胰岛素的细胞因细胞凋亡而死亡，导致对胰岛素的依赖。然而，这些事件 促进？？细胞死亡的机制仍不完全清楚。为了开发新的有效的糖尿病治疗方法，必须增加我们对调节β细胞存活过程的基本知识。 病人。有证据表明，女性荷尔蒙17？雌二醇(雌二醇)可以保护胰岛素的产生并预防糖尿病。虽然雌二醇主要通过两种不同的雌激素受体起作用 最近，G蛋白偶联雌激素受体(GPER)，也被称为GPR30，被认为是一种可能的雌激素膜受体，介导一系列的 非基因组的E2信号。这些内质网在保护？细胞存活中的个体作用尚未确定。我们的探索性应用程序的目标是阐明 通过使用小鼠遗传模型，在活体内通过GPER发挥非经典雌激素作用。我们将使用一个组合的细胞特异性ERpha/ERbeta缺陷小鼠(？ERabKO)和一只GPER缺陷小鼠。利用这些工具，结合药理学探针，我们将研究GPER在体内和培养的胰岛中对β细胞存活的作用。通过这项拟议的研究--这是第一次研究快速的、非基因组的ER在活体内的细胞存活--我们计划证明GPER对于活体内的细胞存活是重要的，因此代表了治疗干预的一个可行的靶点。

In diabetes, the death of insulin-producing ß-cells in the pancreas by apoptosis leads to insulin dependence. Yet, the events that promote ß-cell death are still not fully understood. It is essential to increase our basic knowledge of the processes regulating beta-cell survival in order to develop novel and efficient therapies for diabetic patients. Evidence suggests that the female hormone, 17 ß-estradiol (estradiol), protects insulin production and prevents diabetes. Although estradiol acts primarily via two distinct estrogen receptors (ERs), ERalpha and ERbeta, recently, the G protein-coupled estrogen receptor (GPER), also called GPR30 has been recognized as a putative membrane receptor for estrogens that mediates a series of non-genomic E2 signals. The individual contributions of these ERs in protecting ß-cell survival have not been established. Our objective for this exploratory application is to elucidate the contribution played by non-classical estrogen actions via GPER in ß-cell survival in vivo, through the use of genetic mouse models. We will use a combined ß-cell specific ERalpha/ERbeta deficient mouse (ßERabKO) and a GPER deficient mouse. Using these tools, in combination with pharmacological probes, we will study the role of GPER actions in beta-cell survival in vivo and in cultured islet. Through the proposed research - which is the first investigation of rapid, non genomic ERs in ß-cell survival in vivo - we plan to demonstrate that GPER is important to ß-cell survival in vivo, and therefore represent a viable targets for therapeutic intervention.