Botanical Estrogens: Mechanisms, Dose and Target Tissues

描述（由申请人提供）：植物性雌激素被女性广泛使用，她们期望它们提供一种安全、天然的雌激素来源，以取代绝经期内源性雌激素的损失。因为雌激素对靶细胞有不同的影响，包括对某些乳腺癌的刺激，这种不受管制的植物性雌激素的摄入可能并不一定会导致健康的衰老。雌激素调节许多生殖和非生殖组织的基因转录程序和生理，其作用机制是多方面的，涉及两种雌激素受体，ERa和ER，核启动和核外启动，激酶介导的途径。对于植物性雌激素，人们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提供我们将研究的植物性雌激素的分子和细胞活性概况，这些植物性雌激素来自大豆、野生山药、甘草根和冬葵，以确定这些植物性雌激素是否具有与雌二醇或选择性雌激素受体调节剂（SERMs）相似或不同的活性。在Aim 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ERa和ER¿的分子相互作用。在目标2中，我们将在全基因组基础上研究植物雌激素如何通过核和核外途径调节靶细胞中内质网和蛋白激酶募集到染色质结合位点（池孔）的模式以及基因表达（转录组）的变化。在Aim 3中，我们将生成机制系统生物学概况，将植物雌激素的基质、转录组和途径特异性作用与它们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性雌激素的反应建立在一个坚实的机制基础上，从而确定植物性雌激素是否与其他雌激素具有相似或独特的活性，并为未来的临床研究提供基础信息。我们的机制和细胞研究结果也将指导和解释P50计划中其他项目的工作。

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.