Botanical Estrogens: Mechanisms, Dose and Target Tissues

描述（由申请人提供）：植物性雌激素被妇女广泛食用，期望它们提供安全、天然的雌激素来源，以替代绝经期内源性雌激素的损失。由于雌激素对靶细胞有不同的影响，包括刺激某些乳腺癌，这种不受管制的植物雌激素消费可能不会均匀地促进健康衰老。雌激素调节基因转录程序和许多生殖和非生殖组织的生理学，它们的作用机制是多方面的，涉及两种雌激素受体ER α和ER <$，以及核启动和核外启动的激酶介导的途径。对于植物雌激素，对这些机制和细胞方面知之甚少。我们的总体目标是使用系统生物学方法来提供我们将研究的植物雌激素的活性的分子和细胞概况，从大豆，野山药，甘草根和当归，以确定这些植物雌激素是否具有与雌二醇或选择性雌激素受体调节剂（SERM）相似或不同的活性。在目标1中，我们将通过分析配体结合，配体-受体复合物的构象和动力学，以及它们与关键共调节蛋白的相互作用来研究植物雌激素与ER α和ER？的分子相互作用。在目标2中，我们将研究如何ER和蛋白激酶的招聘模式染色质结合位点（顺式）和基因表达的变化（转录组）在靶细胞中的植物雌激素通过核和胞核途径在全基因组的基础上进行调节。在目标3中，我们将生成机制系统生物学配置文件，将植物雌激素的顺式，转录组和路径特异性作用与其对细胞功能特性的影响联系起来。通过这种方式，我们将能够将细胞对植物雌激素的反应置于一个坚实的机制基础上，这将允许确定植物雌激素是否具有与其他雌激素相似或独特的活性，并为未来的临床研究提供基本信息。我们的机制和细胞研究结果也将在指导和解释这个P50计划的其他项目中的工作。 公共卫生相关性：人们对植物雌激素的有效性和安全性知之甚少，这些雌激素被广泛用于缓解妇女的更年期症状。通过该项目产生的植物雌激素系统生物学概况将为确定植物雌激素是否具有与其他雌激素相似或独特的活性提供关键的机制信息和新的概念框架。

DESCRIPTION (provided by applicant): Botanical estrogens are widely consumed by women with the expectation that they provide a safe, natural source of estrogens to replace the loss of endogenous estrogen in the menopause. Because estrogens can have diverse effects in target cells, including the stimulation of some breast cancers, this unregulated consumption of botanical estrogens might not contribute uniformly to healthy aging. Estrogens regulate gene transcriptional programs and the physiology of many reproductive and non-reproductive tissues, and the mechanisms by which they act are multi-faceted, involving two estrogen receptors, ERa and ER¿, and nuclear-initiated and extra-nuclear-initiated, kinase-mediated pathways. With botanical estrogens, little is known about these mechanistic and cellular aspects. Our overall goal is to use a systems biology approach to provide a molecular and cellular profile of the activity of the botanical estrogens we will be studying, from soy, wild yam, licorice root, and dong quai, to enable determination of whether these botanical estrogens have activities similar to or distinct from estradiol or selective estrogen receptor modulators (SERMs). In Aim 1, we will examine the molecular interactions of botanical estrogens with ERa and ER¿ by analysis of ligand binding, conformation and dynamics of the ligand-receptor complexes, and their interaction with key co-regulatory proteins. In Aim 2, we will examine how the patterns of ER and protein kinase recruitment to chromatin binding sites (cistromes) and changes in gene expression (transcriptomes) in target cells are regulated by botanical estrogens through nuclear and extranuclear pathways on a genome-wide basis. In Aim 3, we will generate mechanistic systems biology profiles that relate the cistromes, transcriptomes, and pathway-specific actions of botanical estrogens to their effects on cell functional properties. In this way, we will be able to place cell response to botanical estrogens on a firm mechanistic basis that will allow determination of whether botanical estrogens have similar or unique activities from those of other estrogens and provide fundamental information to inform future clinical studies. Our mechanistic and cellular findings will also be relevant in guiding and interpreting the work in other projects in this P50 program. PUBLIC HEALTH RELEVANCE: Little is known about the efficacy and safety of botanical estrogens that are being widely consumed by women for relief from menopausal symptoms. The botanical estrogen systems biology profiles generated through this project will provide crucial mechanistic information and a new conceptual framework for determining whether botanical estrogens have similar or unique activities from those of other estrogens.