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

描述(申请人提供)：糖尿病患者体内产生胰岛素的细胞死亡 胰腺细胞凋亡导致胰岛素依赖。然而，促进细胞死亡的事件仍然存在 没有完全理解。增加我们对调节细胞的过程的基本知识是至关重要的 为糖尿病患者开发新的有效治疗方法。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，预防糖尿病。 虽然雌二醇主要通过两种不同的雌激素受体(ER)发挥作用，但个体 这些内质网在保护细胞存活中的作用尚未确定。我们的长期目标是 确定如何通过调节雌激素信号来保护糖尿病患者的胰岛素产生 以不分性别的方式采取的路径。我们这项申请的目标是阐明 ERA、ER和非经典雌激素作用在细胞存活和胰岛素中的作用 在体内生产，通过使用遗传小鼠模型。根据我们已有的初步数据 我们的假设是，ERA保护细胞存活；而ER则降低ERA的功能和 刺激细胞凋亡。为了验证这一假设，我们将首先使用一只细胞ERA缺陷的小鼠 (ERaKO)证明选择性消除细胞中的ERA会损害胰岛素的产生和 会引发糖尿病。接下来，我们将研究一只ER缺陷小鼠(ER KO)，以证明 相反，选择性地消除内质网细胞中的内质网可以改善胰岛素的产生并预防糖尿病。 最后，我们将创造一个联合的细胞特异性ERA/ER基因敲除小鼠(Era KO)。使用这最后一个 我们将证明，在缺乏经典ERA和ER细胞的情况下，雌二醇具有保护作用 通过涉及一种新的膜内质网的非基因组作用产生胰岛素和预防糖尿病。 通过这项拟议的研究--这是首次研究内质网在体内细胞存活中的作用--我们 计划证明经典和非经典雌激素受体对细胞存活很重要 在体内，因此是治疗干预的可行靶点。

DESCRIPTION (provided by applicant): In diabetes, the death of insulin-producing ¿-cells in the pancreas by apoptosis leads to insulin dependence. Yet, the events that promote ¿-cell death are still not fully understood. It is essential to increase our basic knowledge of the processes regulating ¿-cell survival in order to develop novel and efficient therapies for diabetic patients. Evidence suggests that the female hormone, 17¿-estradiol (estradiol), protects insulin production and prevents diabetes. Although estradiol acts primarily via two distinct estrogen receptors (ERs), ERa and ER¿, the individual contributions of these ERs in protecting ¿-cell survival have not been established. Our long-term goal is to determine how to protect insulin production in diabetic patients by modulating estrogen signaling pathways in a gender non-specific manner. Our objective for this application is to elucidate the respective roles played by ERa, ER¿, and non-classical estrogen actions in ¿-cell survival and insulin production in vivo, through the use of genetic mouse models. Based on the preliminary data we have generated, our hypothesis is that ERa protects ¿-cell survival; whereas, ER¿ reduces ERa function and provokes ¿-cell apoptosis. In order to test this hypothesis, we will first use a ¿-cell ERa deficient mouse (¿ERaKO) to demonstrate that selective elimination of ERa in ¿-cells impairs insulin production and provokes diabetes. Next, we will study a ¿-cell ER¿ deficient mouse (¿ER¿KO) to demonstrate that conversely, selective elimination of ER¿ in ¿-cells improves insulin production and prevents diabetes. Finally, we will create a combined ¿-cell specific ERa/ER¿ knockout mouse (¿ERa¿KO). Using this last model we will demonstrate that in absence of the classical ERa and ER¿ in ¿-cells, estradiol protects insulin production and prevents diabetes via non-genomic actions involving a novel membrane ER. Through the proposed research - which is the first investigation of ERs in ¿-cell survival in vivo - we plan to demonstrate that classical and non-classical estrogen receptors are important to ¿-cell survival in vivo, and therefore represent viable targets for therapeutic intervention.