PHYTOESTROGEN ACTION THROUGH ESTROGEN RECEPTORS a & B

植物雌激素通过雌激素受体发挥作用

• 批准号: 6856243
• 负责人: JOHN A. KATZENELLENBOGEN
• 金额: $ 29.68万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856243
• 关键词: aging; conformation; estradiol; estrogen receptors; flavones; gene expression; hormone regulation /control mechanism; ligands; nutrition related tag; pharmacokinetics; phytoestrogens; soybeans

Phytoestrogens, present in soy-based products, are being consumed by humans in increasing quantities; particularly by women tasking soy isoflavones concentrates for relief of menopausal symptoms. The long-term health effects of this exposure are not known, but because phytoestrogens likely share many of the biological effects of endogenous and synthetic estrogens, they might share their detrimental as well as beneficial effects. The pharmacology of estrogens is complex, however, and not all estrogens have the same profile of beneficial vs. detrimental activities as does estradiol, the endogenous estrogen. Estrogen action is also mediated by two estrogen receptors, ERalpha and ERbeta, proteins that have different tissue distributions and regulated somewhat different sets of genes. ERalpha and ERbeta also respond differently to subtype-selective ligands, an issue of importance because phytoestrogens have a more distinct preference for ERbeta than estradiol. This Project is part of a Research Program Project whose overall goal is to evaluate the long-term health effects that phytoestrogen exposure might have in aging women, using appropriate animal models for breast cancer, lipid metabolism, and cognition. The aims of this Project are: (1) to characterize on a genome-wide basis the pattern of genes that are regulated by the various phytoestrogens through ERalpha and ERbeta in target cells and tissues, and how this pattern compares with regulation by estradiol and other estrogens, (2) to define how the phytoestrogens (as opposed to estradiol and other estrogens) bind to and regulate the conformation and coregulator interaction of the two estrogen receptors, ERalpha and ERbeta, including identifying the specific co-regulator proteins through which these phytoestrogen-receptor complexes than act at specific promoter sites, using novel fluorescence methods developed in our laboratories, and (3) to use novel pharmacological tools, namely specific agonists and antagonists of ERalpha and ERbeta developed in our laboratories, as defined hormonal probes to assess the balance of phytoestrogen action through the two ER subtypes. The results of this project should provide important information on the manner in which phytoestrogens regulate gene expression through ERalpha and ERbeta, in comparison with that of other natural and synthetic estrogens. This information will be useful in evaluating the long-term health effects of phytoestrogen exposure in aging women.

以大豆为基础的产品中存在的植物雌激素正在被人类越来越多地消费；特别是为缓解更年期症状而服用大豆异黄酮浓缩物的妇女。这种暴露对健康的长期影响尚不清楚，但由于植物雌激素可能与内源性和合成雌激素的许多生物学效应相同，它们可能既有有益的影响，也有有害的影响。然而，雌激素的药理学是复杂的，并不是所有的雌激素都像内源性雌激素雌二醇那样具有相同的有益和有害活动。雌激素的作用也是由两种雌激素受体ERα和ERβ介导的，这两种蛋白质具有不同的组织分布，并调节着略有不同的基因集。ERpha和ERbeta对亚型选择性配体的反应也不同，这是一个重要的问题，因为植物雌激素对ERbeta的偏好比雌二醇更明显。 这个项目是一个研究项目的一部分，该项目的总体目标是使用适当的乳腺癌、脂肪代谢和认知的动物模型来评估植物雌激素暴露对老年女性可能产生的长期健康影响。这个项目的目标是：(1)在全基因组的基础上描述在靶细胞和组织中通过ERpha和ERbeta受各种植物雌激素调控的基因的模式，以及这种模式与雌二醇和其他雌激素的调控相比如何；(2)确定植物雌激素(相对于雌二醇和其他雌激素)如何与两种雌激素受体ERpha和ERbeta的构象和共同调节相互作用，包括利用我们实验室开发的新的荧光方法，识别这些植物雌激素受体复合体通过其作用于特定启动子位置的特定共调节蛋白，以及(3)使用新的药理学工具，即我们实验室开发的ERα和ERβ的特定激动剂和拮抗剂，正如定义的激素探针一样，通过这两种ER亚型评估植物雌激素作用的平衡。 与其他天然和合成雌激素相比，该项目的结果应提供有关植物雌激素通过ERa和ERbeta调节基因表达的方式的重要信息。这一信息将有助于评估老年女性暴露于植物雌激素的长期健康影响。