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.

植物性雌激素被广泛消费的妇女与期望，他们提供一个安全，天然， 雌激素的来源，以取代绝经期内源性雌激素的损失。因为雌激素可以 在靶细胞中有不同的作用，包括刺激一些乳腺癌，这种不受调节的 食用植物雌激素可能并不均匀地有助于健康衰老。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 β， 核启动的和非核启动的激酶介导的途径。对于植物雌激素， 了解这些机制和细胞方面。我们的总体目标是使用系统生物学方法 为了提供我们将要研究的植物雌激素活性的分子和细胞概况， 大豆、野山药、甘草和当归，以能够确定这些植物雌激素 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aim中 1、通过配体分析研究植物雌激素与雌激素受体α和雌激素受体β的分子相互作用 配体-受体复合物的结合、构象和动力学，以及它们与键的相互作用 辅助调节蛋白在目标2中，我们将研究ER和蛋白激酶募集的模式如何影响ER和蛋白激酶的表达。 染色质结合位点（顺式组）和靶细胞中基因表达的变化（转录组）是 在全基因组的基础上，通过核和胞核途径由植物雌激素调节。在 目标3，我们将产生机制系统生物学配置文件，涉及顺反子，转录组， 植物雌激素对细胞功能特性影响的途径特异性作用。这样我们 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， 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础信息。我们的机制和细胞发现 也将对P50项目中其他项目的工作起到指导和解释的作用。