Estrogen Receptor Coligand Reprogramming of Menopausal Hormone Therapy

更年期激素治疗的雌激素受体辅配体重编程

• 批准号: 9140165
• 负责人: DALE C LEITMAN
• 金额: $ 18.01万
• 依托单位: IATERION, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-25 至 2017-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140165
• 关键词: Abdomen; Adverse event; Alzheimer' s Disease; Animals; Binding; Binding Sites; Blood; Breast; Breast Cancer Cell; Cell Count; Cell Culture Techniques; Cell Line; Cell Proliferation; Cells; Chronic; Chronic Disease; Clinical Research; Combined Modality Therapy; Complex; Cultured Cells; Data; Development; Diabetes Mellitus; Drug Combinations; Drug Kinetics; Endometrial Carcinoma; Estradiol; Estriol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Estrone; Ethinyl Estradiol; Event; Exposure to; Fatty acid glycerol esters; Female; Flow Cytometry; Fracture; Gene Expression; Genes; Goals; Growth; Health; Hot flushes; Incidence; Lead; Life; Life Expectancy; Ligands; Longevity; MCF7 cell; Mammary gland; Measures; Mediating; Menopause; Metabolic; Metabolic syndrome; Molecular Conformation; Molecular Models; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oncogene Activation; Osteitis; Osteoporosis; Osteoporosis prevention; Pharmaceutical Preparations; Pharmacodynamics; Phase; Ploidies; Postmenopause; Prevention; Primary Prevention; Production; Proliferation Marker; Raloxifene; Regimen; Risk; Safety; Selective Estrogen Receptor Modulators; Serum Markers; Stroke; Surface; Symptoms; Temperature; Testing; Tissues; Uterus; Vagina; Vulva; Weight; Weight Gain; Woman; Women' s Health; base; bone; bone cell; cancer cell; cancer risk; cardiovascular risk factor; diabetes risk; hormone therapy; improved; in vivo; inflammatory marker; innovation; interest; malignant breast neoplasm; melting; molecular modeling; novel; prevent; public health relevance; research clinical testing

 DESCRIPTION (provided by applicant): Our goal is to discover drugs that will make menopausal hormone therapy (MHT) safe for long-term treatment of chronic conditions associated with menopause. Due to the increasing longevity of women, menopause has become a critical issue in Women's Health. Life expectancy for women is now 81.2 years. Unlike just a century ago, most women will reach menopause and live approximately one-third of their life after menopause. There are currently 36 million menopausal women in the U.S. and the number is projected to soar to about 50 million in 25 years. Unfortunately, menopause is associated with an increase in the incidence of osteoporosis, obesity, diabetes and metabolic syndrome. Long term exposure to MHT decreases the risk of these conditions. MHT is approved for short-term treatment of hot flashes and vaginal/vulvar symptoms, since long-term treatment with MHT is associated with an increased risk of breast cancer, cardiovascular risks and Alzheimer's disease. A major breakthrough in primary prevention for Women's Health would occur if safer MHT regimens could be developed for long-term treatment. We discovered compounds termed ERα coligands that reprogram the effects of estradiol on gene expression and cell proliferation. Our data indicate that the ERα coligand binds to the surface of ERα, at a separate binding site than estrogens, leading to an increase in binding of E2 to its binding site. The binding of both ligands simultaneously to ERα produces a change in conformation as demonstrated by an alteration in the melting temperature of ERα. These studies indicate that the conformation of the E2-ERα-ER coligand complex is distinct from the E2-ERα complex leading to the reprogramming of the E2 transcriptional and cellular effects. In fact, we found that the E2/ERα coligand combination reprograms E2 to regulate over 800 unique genes in U2OS cells. These genes are not regulated by E2 or the ERα coligand alone. It is well established that E2 stimulates the proliferation of MCF-7 breast cancer cells by binding to ERα resulting in the activation of oncogenes, such as c-MYC. We found that the ERα coligand reprograms ERα so E2 no longer causes cell proliferation, nor does it stimulate c-MYC production. The ERα coligand also blocked E2 stimulation of uterine growth in mice. Based on these findings, we hypothesize that ERα coligands can be combined with existing estrogens, used in MHT, to block the adverse proliferative action of E2 to allow the ERα coligand/estrogen combination to be used safely for long-term MHT treatment. The aim of this phase I proposal is to select a lead ERα coligand/estrogen combination that has the best safety profile in cultured cells and animals prior to advancing it to Pharmacokinetic/Pharmacodynamic and other pre-clinical testing in a phase II proposal. These studies have the potential to facilitate the early development of a new type of MHT, that can be used for long-term administration, to prevent chronic diseases associated with menopause, such as osteoporosis, obesity, diabetes and metabolic syndrome.

 描述（由适用提供）：我们的目标是发现可以使更年期马龙治疗（MHT）安全的药物安全，可长期治疗与绝经相关的慢性疾病。由于妇女的寿命不断增加，绝经已成为妇女健康中的关键问题。女性的预期寿命现在已有81。2年。与一个世纪前不同，大多数妇女将到达更年期，并在美国更年期妇女之后生活约三分之一，目前预计该数字在25年内飙升至约5000万。不幸的是，更年期与骨质疏松症，肥胖症，糖尿病和代谢综合征的事件增加有关。长期接触MHT会降低这些条件的风险。 MHT被批准用于短期治疗潮热和阴道/外阴症状，因为长期用MHT治疗与乳腺癌，心血管风险和阿尔茨海默氏病的风险增加有关。如果可以开发安全的MHT方案以进行长期治疗，则将在妇女健康的初级预防中取得重大突破。我们发现了称为ERα辅合物的化合物，这些化合物重新编程了雌二醇对基因表达和细胞增殖的影响。我们的数据表明ERα凸起与ERα表面结合， 单独的结合位点比进化，导致E2与其结合位点的结合增加。两种配体的结合仅与ERα的结合产生会议的变化，如ERα熔化温度的改变所证明。这些研究表明，E2-ERα-ER核能配合物的组成与E2-ERα复合物不同，导致E2转录和细胞效应的重编程。实际上，我们发现 E2/ERα凸孔组合重新编程E2以调节U2OS细胞中的800多个独特基因。这些基因不受E2或ERα胶原的调节。众所周知，E2通过与ERα结合而刺激MCF-7乳腺癌细胞的增殖，从而导致癌基因（例如C-Myc）的激活。我们发现ERα凸胶对ERα进行重新编程，因此E2不再引起细胞增殖，也不会刺激C-MYC的产生。 ERα胶体还阻止了小鼠子宫生长的E2模拟。基于这些发现，我们假设可以将ERα凸胶与MHT中使用的现有进化相结合，以阻止E2的不良增殖作用，以允许ERα胶体/雌激素组合安全地用于长期MHT治疗。该阶段I建议的目的是选择铅ERα核糖体/雌激素组合，该组合在培养的细胞和动物中具有最佳的安全性，然后将其推进到II期提案中的药代动力学/药效学和其他临床前测试。这些研究有可能促进一种可用于长期给药的新型MHT的早期发展，以防止与绝经相关的慢性疾病，例如骨质疏松症，肥胖，糖尿病和代谢综合征。