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使用，她们期望它们能提供一种安全、天然的