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

描述（由申请人提供）：在糖尿病中，胰岛素产生细胞的死亡， 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。这是至关重要的，以增加我们的基本知识的过程调节细胞 生存，以便为糖尿病患者开发新的和有效的疗法。证据表明 雌性激素，17 <$-雌二醇（雌二醇），保护胰岛素的产生和预防糖尿病。 虽然雌二醇主要通过两种不同的雌激素受体（ER），ER α和ER β起作用，但个体 这些ER在保护细胞存活方面的贡献尚未确定。我们的长期目标是 确定如何通过调节雌激素信号来保护糖尿病患者的胰岛素分泌 以不分性别的方式进行。本申请的目的是阐明 ER α、ER <$和非经典雌激素作用在<$-细胞存活和胰岛素中的各自作用 通过使用遗传小鼠模型在体内生产。根据我们掌握的初步数据 产生，我们的假设是ER α保护细胞存活;然而，ER β降低ER α功能， 引起细胞凋亡。为了验证这一假设，我们将首先使用一个细胞ER α缺陷小鼠， （² ERaKO）以证明²细胞中ERa的选择性消除会损害胰岛素的产生， 会引发糖尿病接下来，我们将研究一种ER细胞缺陷小鼠（ER KO），以证明 相反地，选择性地消除细胞中的雌激素受体可以提高胰岛素的产生并预防糖尿病。 最后，我们将建立一个联合的<$-细胞特异性ER α/ER <$$>敲除小鼠（<$ER α <$KO）。利用这最后 模型，我们将证明，在缺乏经典的ER α和ER β细胞，雌二醇保护， 胰岛素的产生和预防糖尿病通过非基因组作用涉及一种新的膜ER。 通过拟议的研究-这是ER在体内细胞存活中的首次调查-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 因此代表了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.