A NOVEL TRANSGENIC MOUSE MODEL FOR DIABETES

一种新型糖尿病转基因小鼠模型

基本信息

批准号：
7052768
负责人：
AMY S LEE
金额：
$ 15.9万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7052768
关键词：
diabetes mellitus genetics disease /disorder model genetic models genetically modified animals glucose metabolism laboratory mouse model design /development noninsulin dependent diabetes mellitus obesity

项目摘要

DESCRIPTION (provided by applicant): This proposal aims to establish a novel transgenic mouse line, referred to as D2D that can serve as a model for the study of diabetes and obesity. Our laboratory has been studying the transcriptional regulation of a glucose regulated protein GRP78 that is a major molecular chaperone localized in the endoplasmic reticulum (ER). To understand how physiological stress activates the Grp78 promoter in vivo, we have created a series of transgenic mouse lines. One of these lines, D2D, contains a genetically modified version of the Grp78 promoter driving the expression of the bacterial lacZ gene encoding for beta-galactosidase. In this line, the lacZ transgene activity is strongly expressed in all pancreatic beta-cells, and some expression is also detected in the liver and brain including the hypothalamus controlling glucose sensing. To our surprise, we discovered that the D2D founder mouse became increasingly obese with age. Further analysis of the founder and its F1 and F2 offspring reveals that the D2D line exhibits properties of type II diabetes and age dependent onset of obesity. Examination of the D2D pancreatic sections showed normal range of beta-cell mass, proliferation and apoptosis. Taken together, our preliminary results suggest that D2D could offer a novel model for type II diabetes and obesity, and provide a new experimental system for the study of beta-cell defect with possible connection to liver and brain problems. In Specific Aim 1, we propose to perform comprehensive analyses of glucose metabolism and phenotypic tests for the D2D mice and two other independently derived lines that exhibit similar but distinct lacZ expression profile. In Specific Aim 2, we will determine the various mechanism(s) that could account for the diabetic phenotype observed in D2D. This pilot project has the potential to identify a new gene critical for glucose homeostasis through integration site analysis of D2D and it will provide the foundation for future studies to decipher the detail mechanism and preclinical applications of the D2D model towards therapy of diabetes and obesity.

描述（由申请人提供）：本提案旨在建立一种新型转基因小鼠品系，称为D2D，可以作为糖尿病和肥胖症研究的模型。我们的实验室一直在研究葡萄糖调节蛋白 GRP78 的转录调控，该蛋白是定位于内质网 (ER) 的主要分子伴侣。为了了解生理应激如何在体内激活 Grp78 启动子，我们创建了一系列转基因小鼠品系。其中一个品系 D2D 包含 Grp78 启动子的转基因版本，驱动编码 β-半乳糖苷酶的细菌 lacZ 基因的表达。在该细胞系中，lacZ转基因活性在所有胰腺β细胞中强烈表达，并且在肝脏和大脑中也检测到一些表达，包括控制葡萄糖传感的下丘脑。令我们惊讶的是，我们发现 D2D 创始人小鼠随着年龄的增长变得越来越肥胖。对创始人及其 F1 和 F2 后代的进一步分析表明，D2D 系表现出 II 型糖尿病和年龄依赖性肥胖发病的特性。 D2D 胰腺切片检查显示 β 细胞质量、增殖和凋亡处于正常范围。总而言之，我们的初步结果表明，D2D 可以为 II 型糖尿病和肥胖症提供一种新模型，并为研究可能与肝脏和大脑问题有关的 β 细胞缺陷提供新的实验系统。在具体目标 1 中，我们建议对 D2D 小鼠和其他两个独立衍生的表现出相似但不同 lacZ 表达谱的品系进行葡萄糖代谢和表型测试的全面分析。在具体目标 2 中，我们将确定可解释 D2D 中观察到的糖尿病表型的各种机制。该试点项目有可能通过 D2D 的整合位点分析来识别对葡萄糖稳态至关重要的新基因，并将为未来研究破译 D2D 模型治疗糖尿病和肥胖症的详细机制和临床前应用奠定基础。