Estrogen receptor signaling in diabetes prevention

雌激素受体信号传导在糖尿病预防中的作用

• 批准号: 6849526
• 负责人: Franck Mauvais-Jarvis
• 金额: $ 15万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6849526
• 关键词: apoptosis; biological signal transduction; disease /disorder prevention /control; estradiol; estrogen receptors; genetically modified animals; insulin; laboratory mouse; laboratory rat; noninsulin dependent diabetes mellitus; oxidative stress; pancreatic islet function; pancreatic islets; raloxifene

DESCRIPTION (provided by applicant): The long term goal of this project is to understand whether modulating E2 actions in a tissue specific manner could be new strategy to prevent type 2 diabetes (T2DM). T2DM and its vascular complications are the consequences of oxidative stress in tissues. There is a large body of evidence demonstrating that the endogenous estrogen, 17beta-estradiol (E2), protects against T2DM in both rodents and humans in conditions of oxidative stress. Women are naturally protected against T2DM until the age of menopause and then develop insulin resistance and an increased risk of T2DM. This phenomenon is reversed by E2 replacement therapy which also leads to a 35% reduction in the incidence of diabetes in predisposed women. E2 protects female rodents from T2DM by a powerful effect on pancreatic beta-cell function/survival. This effect is reproduced by E2 infusion in male rodents. Our preliminary observations suggest that 1) E2 protects male mice against age-related degradation of insulin secretion and diabetes, 2) E2 protects human pancreatic islets from death induced by oxidative stress and that 3) E2 receptors are cytosolic in pancreatic beta-cells, a localization compatible with anti-apoptotic actions. Our hypothesis is that E2 exhibits potent anti-apoptotic actions which protect pancreatic beta-cells from apoptosis in conditions of oxidative stress. These effects are mediated by E2 receptors (ER) and can be mimicked by selective estrogen receptor modulators (SERM) to prevent and cure diabetes in rodents. To address this issue, we propose: 1) To determine whether the SERM, raloxifene, can prevent pancreatic beta-cell destruction in vivo in diabetic rodents. 2) To demonstrate the importance of the ER-alpha in the protection of pancreatic beta-cells from oxidative stressand destruction using knockout mouse models of E2 deficiency andresistance This project seeks support through the exploratory/developmental grant (R21) mechanism in answer to a specific program announcement (PA-02-008): "pilot and feasibility program in Diabetes, Endocrinology and Metabolism".

描述（由申请人提供）：本项目的长期目标是了解以组织特异性方式调节E2作用是否可能是预防2型糖尿病（T2 DM）的新策略。T2 DM及其血管并发症是组织中氧化应激的结果。大量证据表明，内源性雌激素17 β-雌二醇（E2）可在氧化应激条件下保护啮齿动物和人类免受T2 DM的影响。女性在绝经前自然受到保护，不会患上T2 DM，然后出现胰岛素抵抗，患T2 DM的风险增加。这种现象被E2替代疗法逆转，这也导致易感女性糖尿病发病率降低35%。E2通过对胰腺β细胞功能/存活的强大作用保护雌性啮齿动物免受T2 DM的影响。在雄性啮齿类动物中通过E2输注再现了这种效应。我们的初步观察结果表明：1）E2保护雄性小鼠免受年龄相关的胰岛素分泌下降和糖尿病的影响，2）E2保护人类胰岛免受氧化应激诱导的死亡，3）E2受体在胰腺β细胞中存在于胞浆中，这是一种与抗凋亡作用相容的定位。我们的假设是，E2表现出有效的抗凋亡作用，保护胰腺β细胞在氧化应激条件下免于凋亡。这些作用由E2受体（ER）介导，并可被选择性雌激素受体调节剂（SERM）模拟，以预防和治疗啮齿动物的糖尿病。为解决这一问题，我们建议： 1)确定SERM雷洛昔芬是否可以预防糖尿病啮齿动物体内胰腺β细胞破坏。2)为了证明ER-α在保护胰腺β细胞免受氧化应激和破坏中的重要性，使用E2缺乏和抗性的敲除小鼠模型，该项目通过探索性/发展性资助（R21）机制寻求支持，以响应特定的计划公告（PA-02-008）：“糖尿病，内分泌学和代谢的试点和可行性计划”。