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：
7787369
负责人：
Franck Mauvais-Jarvis
金额：
$ 4.89万
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/7787369
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 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 Principal Investigator Production Protocols documentation Qualifying Research Research Personnel Research Proposals Role 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 novel oxidative damage prevent programs receptor tool

项目摘要

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.

在糖尿病中，细胞凋亡在胰腺中产生胰岛素的ß细胞死亡会导致胰岛素依赖性。但是，事件的事件促进ß细胞死亡仍未完全理解。至关重要的是，我们必须提高对预定β细胞生存的过程的基础知识，以开发新颖有效的糖尿病疗法患者。有证据表明，雌性荷花酮17β-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起作用（ERS），Eralpha和Erbeta最近，G蛋白偶联的雌激素受体（GPER），也称为GPR30，已被认为是雌激素的假定膜受体，可介导一系列介导一系列的雌激素非基因组E2信号。这些人在保护β-细胞生存方面的个人贡献尚未建立。我们对此探索性应用的目标是阐明通过使用遗传小鼠模型，在体内通过GPE在体内通过GPER的非古典雌激素作用。我们将使用组合的ß细胞特异性ERALPHA/ERBETA特异性小鼠（ßerabko）和GPER特异性小鼠。使用这些工具，结合了药物问题，我们将研究GPER作用在体内和培养胰岛中生存中的作用。通过拟议的研究（这是对体内ß细胞生存中快速，非基因组生存的首次研究），我们计划证明GPE对体内的ß细胞生存至关重要，因此代表了对治疗干预的可行靶标。