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

植物学的分子机制和细胞途径/Benita S.Katzenellenbogen

• 批准号: 8007123
• 负责人: William G Helferich
• 金额: $ 77.6万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8007123
• 关键词: Affinity; Angelica sinensis preparation; Apoptosis; Back; Behavior; Binding; Binding Sites; Bioinformatics; Biological; Biological Assay; Blood; Botanicals; Cells; Chromatin; Clinical Research; Complex; Consumption; Dose; Drug Kinetics; Endocrinology; Equilibrium; Estradiol; Estrogen Receptors; Estrogens; Exposure to; Future; Gene Expression; Gene Expression Profile; Genes; Goals; Health; Hormonal; Hormone Responsive; Human; Label; Laboratories; Licorice; Ligand Binding; Ligands; MAPK Signaling Pathway Pathway; MAPK1 gene; Malignant Neoplasms; Maps; Mediating; Menopausal Symptom; Menopause; Methods; Mitogen-Activated Protein Kinase Kinases; Molecular; Molecular Conformation; Monitor; Nuclear; Outcome; Pathway interactions; Pattern; Phosphotransferases; Physiological; Physiology; Plant Roots; Property; Protein Kinase; Proteins; Raloxifene; Receptor Activation; Receptor Signaling; Regulator Genes; Relative (related person); Safety; Selective Estrogen Receptor Modulators; Signal Pathway; Source; Specialized Center; Staging; Stimulation of Cell Proliferation; Structure; Systems Biology; Tamoxifen; Tissues; Woman; Work; Yam - dietary; base; cell behavior; cell motility; chemical synthesis; estrophilin; expectation; genome-wide; healthy aging; interest; malignant breast neoplasm; metabolic abnormality assessment; older women; programs; receptor; receptor binding; receptor function; reproductive; response; soy; xenoestrogen

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.

植物性雌激素被女性广泛消耗，期望她们提供安全自然 雌激素的来源以取代绝经中内源性雌激素的损失。因为雌激素可以 在靶细胞中具有多种影响，包括刺激某些乳腺癌，这种不受管制 植物雌激素的消费可能不会统一地促进健康的衰老。雌激素调节基因 转录程序以及许多生殖和非生殖组织的生理学以及 它们作用的机制是多方面的，涉及两个雌激素受体，即ERA和ERP，以及 核引发和核外引发的激酶介导的途径。使用植物雌激素，几乎没有 有关这些机械和细胞方面的知名度。我们的总体目标是使用系统生物学方法 为了提供植物雌激素活性的分子和细胞谱，我们将从 大豆，野生山药，甘草根和Dong Quai，以确定这些植物雌激素是否能够确定 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。目标 1，我们将通过分析配体分析植物雌激素与ERP的分子相互作用 配体 - 受体复合物的结合，构象和动力学及其与钥匙的相互作用 促蛋白。在AIM 2中，我们将研究ER和蛋白激酶募集的模式如何 靶细胞中染色质结合位点（CISTROMES）和基因表达（转录组）的变化是 通过核雌激素通过核和核外途径在全基因组的基础上调节。在 AIM 3，我们将生成与Cistromes，Transcriptomes和 植物雌激素对其对细胞功能特性的影响的途径特异性作用。这样，我们 将能够以牢固的机械基础将细胞对植物雌激素的反应放置 确定植物雌激素是否具有与其他雌激素相似或独特的活动 并提供基本信息，以告知未来的临床研究。我们的机械和细胞发现 在该P50计划中的其他项目中，指导和插入工作也将与之相关。