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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，胰腺中产生胰岛素的细胞死亡