PHYTOESTROGEN ACTION THROUGH ESTROGEN RECEPTORS a & B

大豆制品中的植物雌激素正越来越多地被人类消费，特别是那些要求大豆浓缩物来缓解更年期症状的妇女。这种暴露的长期健康影响尚不清楚，但由于植物雌激素可能具有内源性和合成雌激素的许多生物学效应，它们可能具有有害和有益的影响。雌激素的药理学是复杂的，然而，并不是所有的雌激素都具有与内源性雌激素雌二醇相同的有益与有害活性的特征。雌激素作用也由两种雌激素受体ER α和ER β介导，这两种蛋白质具有不同的组织分布并调节稍微不同的基因组。ER α和ER β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ER β的偏好比雌二醇更明显。 该项目是研究计划项目的一部分，其总体目标是评估植物雌激素暴露可能对老年妇女产生的长期健康影响，使用适当的乳腺癌，脂质代谢和认知动物模型。该项目的目标是：（1）在全基因组的基础上表征在靶细胞和组织中由各种植物雌激素通过ER α和ER β调节的基因的模式，以及该模式如何与雌二醇和其他雌激素的调节进行比较，（2）植物雌激素如何（与雌二醇和其他雌激素相反）结合并调节两种雌激素受体ER α和ER β的构象和共调节因子相互作用，包括使用我们实验室开发的新荧光方法鉴定这些植物雌激素-受体复合物通过其作用于特定启动子位点的特定共调节蛋白，和（3）使用新的药理学工具，即我们实验室开发的ER α和ER β的特异性激动剂和拮抗剂，作为确定的激素探针，以评估通过两种ER亚型的植物雌激素作用的平衡。 该项目的结果应提供重要的信息，植物雌激素通过ER α和ER β调节基因表达的方式，与其他天然和合成雌激素相比。这些信息将有助于评估植物雌激素暴露对老年妇女长期健康的影响。

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.