Botanical Estrogens: Mechanisms, Dose and Target Tissues

描述(申请人提供)：植物雌激素被妇女广泛使用，期望它们提供一种安全、自然的雌激素来源，以弥补更年期内源性雌激素的损失。由于雌激素可以对靶细胞产生不同的影响，包括对一些乳腺癌的刺激，这种不受监管的植物雌激素消耗可能不会对健康衰老做出一致的贡献。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，其作用机制是多方面的，涉及两个雌激素受体，Era和ER，以及核启动和核外启动的激酶介导的通路。对于植物雌激素，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来提供我们将研究的来自大豆、野生山药、甘草和冬瓜的植物雌激素活性的分子和细胞图谱，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-受体复合体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，我们将研究在全基因组的基础上，植物雌激素如何通过核和核外途径调节靶细胞中ER和蛋白激酶募集到染色质结合部位(Cstrome)的模式和基因表达的变化(转录本)。在目标3中，我们将生成机制系统生物学简档，将细胞周期、转录本和植物雌激素的路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雌激素的反应建立在坚实的机制基础上，从而能够确定植物雌激素是否具有与其他雌激素类似或独特的活性，并为未来的临床研究提供基础信息。我们的机械和细胞发现也将对指导和解释这个P50计划中的其他项目的工作起到重要作用。 与公共卫生相关：人们对植物雌激素的有效性和安全性知之甚少，这些雌激素正被妇女广泛消费，以缓解更年期症状。通过该项目产生的植物雌激素系统生物学图谱将提供重要的机制信息和一个新的概念框架，以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。

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.