Estrogen Receptor-Selective Herbs for Menopause Symptoms

雌激素受体选择性草药治疗更年期症状

• 批准号: 6765668
• 负责人: DALE C LEITMAN
• 金额: $ 35.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6765668
• 关键词: alternative medicine; athymic mouse; biotherapeutic agent; breast neoplasms; cell proliferation; chromatin immunoprecipitation; clinical research; clinical trials; estrogen receptors; estrogens; high performance liquid chromatography; hot flash; human subject; mass spectrometry; medicinal plants; menopause; neoplastic cell; osteoporosis; patient oriented research; polymerase chain reaction; sign /symptom; transfection

DESCRIPTION (provided by applicant): Our long-term objective is to identify safe and effective natural agents to prevent menopausal symptoms and osteoporosis. Currently, there are 36 million postmenopausal women in the USA, and this number is projected to soar to 50 million by the year 2020. Menopause is characterized by severe estrogen deficiency, which leads to hot flushes, vaginal dryness, mood swings and osteoporosis. Although these conditions have been effectively treated with hormone replacement therapy (HILT) for the past 50 years, recent clinical trials have found that HRT is associated with increased risk of breast cancer, cardiovascular disease and dementia. The failure of HRT to live up to expectations has left the rapidly expanding menopausal population without a good alternative that prevents both hot flushes and osteoporosis. Thus, there is a tremendous need to discover more selective and safer estrogens. Many women seek alternatives to HRT, particularly estrogens derived from plants, known as phytoestrogens. Interest in phytoestrogens has been fueled by observational studies showing a lower incidence of menopausal symptoms, osteoporosis, cardiovascular disease and breast cancer in Asian women who consume soy and herbal products. Unfortunately, little scientific data exists to show that they are effective at preventing menopausal symptoms and osteoporosis. Based on our studies showing that estrogen receptor (ER) alpha mediates breast cancer cell proliferation and ERBeta inhibits proliferation and breast tumor formation in mouse xenografts, we are using molecular biology techniques to identify herbs that exhibit selective estrogenic activity for ERBbeta. We hypothesize that ERBeta-selective estrogens will be safer than estrogens found in current HRT regimens that interact non-selectively with ERalpha and ERBeta, and will be effective at reducing hot flushes and osteoporosis. To discover ERbeta-selective herbs, we screened 67 Chinese herbs using transient transfection assays with luciferase reporters in the presence of ERalpha or ERBeta Seven herbs selectively regulated transcription with ERli Some of these herbs also recruited the coregulator, GRIP1 to ERBeta, and were very weak at causing the proliferation of MCF-7 breast cancer cells. The goals of this proposal are to: (1) employ molecular biology techniques to determine how herbs are ER-selective and if the herbs retain ER-selectivity in vivo. (2) identify active compounds in herbs responsible for ER-selectivity. (3) identify which class of ER-selective herbs are most effective at reducing the frequency and severity of hot flushes. Identifying ER-selective herbs could lead to the discovery of novel agents that retain the beneficial effects on bone and menopausal symptoms, but lack the cancer promoting properties of estrogens in current HRT on the breast and endometrium.

描述（由申请人提供）：我们的长期目标是确定安全有效的天然药物，以预防更年期症状和骨质疏松症。目前，美国有3600万绝经后妇女，预计到2020年这一数字将飙升至5000万。更年期的特征是严重的雌激素缺乏，导致潮热，阴道干燥，情绪波动和骨质疏松症。虽然这些条件已经有效地治疗激素替代疗法（HILT）在过去的50年里，最近的临床试验发现，HRT与乳腺癌，心血管疾病和痴呆症的风险增加。HRT的失败辜负了人们的期望，使迅速扩大的绝经人口没有一个很好的替代品，防止潮热和骨质疏松症。因此，非常需要发现更具选择性和更安全的雌激素。许多妇女寻求替代激素替代疗法，特别是来自植物的雌激素，称为植物雌激素。观察性研究表明，食用大豆和草药产品的亚洲妇女的更年期症状、骨质疏松症、心血管疾病和乳腺癌的发病率较低，这激发了人们对植物雌激素的兴趣。不幸的是，几乎没有科学数据表明它们能有效预防更年期症状和骨质疏松症。基于我们的研究表明，雌激素受体（ER）α介导的乳腺癌细胞增殖和ERBeta抑制增殖和乳腺肿瘤形成的小鼠异种移植物，我们正在使用分子生物学技术，以确定草药，表现出选择性雌激素活性的ERBbeta。我们假设ER β选择性雌激素比目前HRT方案中发现的雌激素更安全，后者与ER α和ER β非选择性相互作用，并有效减少潮热和骨质疏松症。为了发现ER β选择性草药，我们在ER α或ER β存在下使用荧光素酶报告基因的瞬时转染试验筛选了67种中药。7种草药选择性地用ER β调节转录。这些草药中的一些还招募了辅助调节因子GRIP 1至ER β，并且在引起MCF-7乳腺癌细胞增殖方面非常弱。本研究的目的是：（1）利用分子生物学技术来确定中药是如何具有ER选择性的，以及中药在体内是否保留了ER选择性。(2)鉴定草药中负责ER选择性的活性化合物。(3)确定哪类ER选择性草药在减少潮热的频率和严重程度方面最有效。识别ER选择性草药可能会导致发现新的药物，保留对骨和更年期症状的有益作用，但缺乏目前HRT中雌激素对乳腺和子宫内膜的促癌特性。