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

雌激素受体在胰腺β细胞存活和胰岛素分泌中的作用

基本信息

批准号：
7615652
负责人：
Franck Mauvais-Jarvis
金额：
$ 27.38万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-15 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7615652
关键词：
Apoptosis Biology Cell Death Cell Survival Cells Cessation of life Data Dependence Development Diabetes Mellitus Estradiol Estrogen Receptors Estrogens Event Female Gender Genetic Goals Gonadal Steroid Hormones Health Hormones Human In Vitro Incidence Individual Insulin Investigation Knockout Mice Knowledge Membrane Mission Mitochondria Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pancreas Pathway interactions Physiological Physiological Processes Physiology Play Process Production Protocols documentation Qualifying Research Research Personnel Research Proposals Role Signal Pathway Staging Streptozocin Structure of beta Cell of islet Testing Therapeutic Therapeutic Intervention United States National Institutes of Health base cell injury cytokine diabetic diabetic patient experience improved in vivo innovation insulin secretion islet mouse model non-genomic novel oxidative damage prevent programs receptor tool

项目摘要

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.

描述（由应用程序提供）：在糖尿病中，产生胰岛素的死亡 - e- 细胞凋亡的胰腺导致胰岛素依赖性。然而，促进死亡的事件仍然是不完全理解。重要的是要增加我们对调节过程的基本知识� -cell 为了为糖尿病患者开发新颖有效的疗法而生存。有证据表明这一点雌马17？ - 雌二醇（雌二醇）可保护胰岛素的产生并预防糖尿病。尽管雌二醇通过两个不同的雌激素受体（ERS），ERA和ER？这些人在保护保护生存方面的贡献尚未建立。我们的长期目标是通过调节雌激素信号来确定如何保护糖尿病患者的胰岛素产生以性别非特异性方式的途径。我们对此应用的目标是阐明 ERA，ERâ和非经典雌激素作用 - 细胞生存和胰岛素通过使用遗传小鼠模型在体内生产。根据初步数据产生的是，我们的假设是时代保护了 - 细胞生存；而erThe则降低了时代的功能和挑衅 - 细胞凋亡。为了检验这一假设，我们将首先使用`` - 细胞时''不足鼠标（»eRako）证明，选择性消除ERA中的ERA» - 细胞会损害胰岛素的产生和挑衅糖尿病。接下来，我们将研究A� -cell erT防御鼠标（Er¿ko），以证明相反，在�-细胞中选择性消除ER？可以改善胰岛素的产生并预防糖尿病。最后，我们将创建一个组合的 - 细胞特定时代/埃尔淘汰鼠标（ERA¿KO）。最后使用此模型我们将证明，在缺乏经典时代和埃尔德中，雌二醇保护胰岛素产生并通过涉及新膜ER的非基因组作用来阻止糖尿病。通过拟议的研究 - 这是对体内细胞生存中ER的首次研究 - 我们计划证明经典和非经典雌激素受体对–细胞存活很重要体内，因此代表了治疗干预的可行靶标。