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：
7408547
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/7408547
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 Patients Physiological Physiological Processes Physiology Process Production Protocols documentation Qualifying Research Research Personnel Research Proposals Role Role playing therapy 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 experience improved in vivo innovation insulin secretion islet mouse model non-genomic novel 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（由申请人提供）：在糖尿病中，产生胰岛素的细胞死亡 ¿ - 细胞在胰腺细胞凋亡导致胰岛素依赖，然而，促进的事件 ¿ -细胞死亡仍在没有完全理解，有必要增加我们对调节过程的基本了解。 -细胞证据表明，为糖尿病患者开发新颖有效的疗法。女性荷尔蒙，17¿ -雌二醇（estradiol），保护胰岛素的产生并预防糖尿病。尽管雌二醇主要通过两种不同的雌激素受体 (ER)、ERa 和 ER¿ , 个人这些 ER 在保护 ¿ -我们的长期目标尚未确定。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我们此应用程序的目标是阐明非特定性别的途径。 ERa、ER¿ 各自扮演的角色，以及 ¿ 中的非经典雌激素作用-细胞存活和胰岛素根据我们掌握的初步数据，通过使用遗传小鼠模型进行体内生产。生成，我们的假设是 ERa 保护 ¿ -细胞存活；而，ER¿ ERa 降低功能并挑衅 ¿ -细胞凋亡为了检验这个假设，我们首先使用 ¿ -细胞ERa缺陷小鼠 (¿ERaKO) 证明 ¿ 中 ERa 的选择性消除-细胞损害胰岛素的产生和接下来，我们将研究 ¿ -细胞ER¿有缺陷的鼠标（¿ER¿KO）来证明相反，选择性消除 ER¿在 -细胞提高胰岛素的产生并预防糖尿病。最后，我们将创建一个组合 ¿ -细胞特异性ERa/ER¿使用最后一个基因敲除小鼠（¿ERa¿KO）。模型我们将证明在没有经典 ERa 和 ER¿在 - 雌二醇保护细胞通过涉及新型膜 ER 的非基因组作用产生胰岛素并预防糖尿病。通过拟议的研究 - 这是对 ER 的首次调查 ¿ -体内细胞存活-我们计划证明经典和非经典雌激素受体对于 ¿ -细胞存活体内，因此代表了治疗干预的可行目标。