Molecular Mechanisms and Cellular Pathways of Botanical/Benita S.Katzenellenbogen

植物雌激素被女性广泛食用，期望它们能提供一种安全、自然的 雌激素的来源，以补充更年期内源性雌激素的损失。因为雌激素可以 对靶细胞有不同的作用，包括刺激一些乳腺癌，这是不受调控的 植物雌激素的摄入可能并不一致地对健康衰老做出贡献。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学，以及 它们的作用机制是多方面的，涉及两种雌激素受体，ERA和ERP，以及 核启动和核外启动，激酶介导的通路。对于植物性雌激素，几乎不是 了解这些机械和细胞方面的知识。我们的总体目标是使用系统生物学方法 为了提供我们将研究的植物雌激素活性的分子和细胞概况，从 大豆、野山药、甘草和冬瓜，以确定这些植物雌激素是否 具有与雌激素或选择性雌激素受体调节剂(SERM)相似或不同的活性。在AIM 1、我们将通过配基分析来研究植物雌激素与era和erp的分子相互作用。 配体-受体复合体的结合、构象、动力学及其与键的相互作用 共调节蛋白。在目标2中，我们将研究ER和蛋白激酶募集的模式是如何 靶细胞的染色质结合部位(Cstrome)和基因表达的变化(转录体)是 在全基因组的基础上，由植物雌激素通过核和核外途径进行调节。在……里面 目标3，我们将生成机制系统生物学配置文件，将细胞周期、转录本和 植物雌激素对细胞功能特性影响的途径特异性作用。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械基础上，这将使 测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。我们的机械和细胞发现 也将在指导和介入P50计划中的其他项目中的工作方面发挥作用。

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 ERp, and nuclear-initiated and extranuclear-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 ofthe 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 ERp by analysis of ligand binding, conformation and dynamics ofthe ligand-receptor complexes, and their interaction with key coregulatory 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 interpeting the work in other projects in this P50 program.