Safety and Molecular Mechanisms of CDB-2914

CDB-2914的安全性和分子机制

• 批准号: 7284735
• 负责人: PATRICIA L. MORRIS
• 金额: $ 37.98万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284735
• 关键词: Affect; Agonist; Androgen Receptor; Androgens; Applications Grants; Biopsy; Breast; Breast Diseases; CDB 2914; Cell Cycle; Cell Cycle Kinetics; Cell Line; Cell model; Cell physiology; Cells; Characteristics; Class; Clinical; Clinical Research; Clinical Trials; Combined Oral Contraceptives; Conceptions; Contraceptive Agents; Contraceptive methods; Cytoplasmic and Nuclear Receptors; Development; Dose; Duct (organ) structure; Endometrial; Endometrial Carcinoma; Endometrium; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Estrogen Receptor beta; Estrogens; Evaluation; Exposure to; Feasibility Studies; Flow Cytometry; Gene Expression; Genes; Goals; Growth; Growth Factor; Health; Healthcare; Hemorrhage; High Risk Woman; Histology; Hormone replacement therapy; Hormones; Human; Incidence; Intrauterine Devices; Investigation; Ligands; Malignant Epithelial Cell; Mammary Gland Parenchyma; Mammary Tumorigenesis; Mammary gland; Measures; Medroxyprogesterone 17-Acetate; Modeling; Molecular; Molecular Models; Mus; Muscle Cells; Myoma; Myometrial; Normal tissue morphology; Oral Contraceptives; Ovulation; Pattern; Phase; Phase II Clinical Trials; Physiological; Population; Post-Menopausal Hormone Replacement Therapy; Postmenopause; Prevention; Progesterone; Progesterone Receptors; Progestins; Progress Reports; Proliferating; Proliferation Marker; Protein Isoforms; Proteomics; Publishing; Range; Rattus; Reproductive Health; Research; Role; Safety; Serum; Small Interfering RNA; Stanolone; Stem cells; Steroid Receptors; Steroids; Synthetic Progestogens; System; Thick; Time; Tissue Sample; Tissues; Uterine Fibroids; Vaginal Ring; Vascular Endothelial Growth Factors; Vascularization; Week; Woman; cancer cell; cancer risk; clinical application; concept; cytokine; day; emergency contraception; endometriosis; hormone therapy; in vivo; malignant breast neoplasm; molecular modeling; prevent; receptor; receptor expression; reproductive; research clinical testing; response; stem; tumor

Project III: Selective Progesterone Receptor Modulators (SPRMs) represent a new class of progesterone receptor (PR) ligands that range from full PR antagonists to compounds with mixed agonist/antagonist activities on various progesterone target tissues in vivo. Due to diverse effects on the PR, specific PRMs are being investigated for multiple clinical applications in reproductive health care. Potential clinical applications of SPRMs include emergency contraception, long-term estrogen-free contraception and post-menopausal hormone therapy, and treatments for myomas, endometriosis and hormone-dependent tumors. The proposed studies combine molecular modeling, translational, and clinical studies to further investigate the clinical safety of CDB-2914 and characterize its effects at a cellular level on hormone target tissues. Aim 1: Establish and characterize responses of normal human mammary epithelial cells (HMEC) using primary culture models to: a) Determine characteristics of cell cycle kinetics after short and long term exposure to CDB-2914, in the presence of E2 and/or P4; b) Determine whether a proliferating population of stem and progenitor cells can be isolated for further study ex vivo to establish long-term safety of CDB-2914 on breast stem cells. Aim 2: Establish and characterize mouse mammary stem and progenitor cell populations as ex vivo models to study effects of CDB-2914 on the breast, studies with a focus on steroid receptor expression and function. Developing a long-term estrogen-free contraception using a PRM that would also prevent P action on the breast is potentially a contraceptive method with dual benefits, i.e., prevention of conception and breast disease. New findings on endometrial effects of PRMs justify further clinical evaluation. Aim 3: The first clinical study will explore the endometrial effects of CDB 2914 delivered from a vaginal ring at a dose blocking ovulation. Endometrial histology and proliferation markers will be determined over time. A second clinical study will evaluate whether sequential 2-week progestin courses after 12-week PRM ring use will reverse any endometrial changes. The third clinical study will evaluate the effects of low doses of CDB- 2914 applied using an intrauterine system to induce only a local effect while a normal ovulation is maintained. Aim 4: Establish a human endometrial epithelial cell (HEEC) model for molecular modeling studies and characterization of the effects of progestins compared to those of CDB-2914 and SPRMs on the endometrium: a) Determine cell cycle-related effects when estrogen is present or absent, comparing the activity of progestins (P4; medroxyprogesterone acetate, MPA) with that of CDB-2914 using several immortalized human endometrial carcinoma cells; b) Compare effects of SPRMs, progestin, estrogen, or sequential hormone exposure on HEEC functions, using gene expression and proteomic analyses. Project III combines basic, translational and clinical studies to further ascertain the safety of CDB-2914 for human use as well as characterization of this PRM's molecular mechanisms.

项目III：选择性孕激素受体调节剂(SPRM)代表了一类新的孕酮 受体(PR)配体，从完全PR拮抗剂到含有混合激动剂/拮抗剂的化合物 体内各种黄体酮靶向组织的活性。由于对公关的影响各不相同，具体的PRM是 正在研究生殖保健中的多种临床应用。潜在的临床应用 SPRM包括紧急避孕、长期无雌激素避孕和绝经后避孕 激素治疗，以及肌瘤、子宫内膜异位症和激素依赖性肿瘤的治疗。这个 建议的研究结合了分子建模、翻译和临床研究，以进一步研究 CDB-2914的临床安全性，并在细胞水平上表征其对激素靶组织的影响。目标1： 原代培养正常人乳腺上皮细胞(HMEC)并鉴定其反应 培养模型：a)确定短期和长期暴露后细胞周期动力学特征 CDB-2914，在E2和/或P4存在的情况下；b)确定茎和 CDB-2914可分离造血祖细胞用于体外进一步研究，以确定CDB-2914对乳房的长期安全性 干细胞。目的2：建立和鉴定小鼠乳腺干细胞和祖细胞群体 CDB-2914对乳腺影响的活体模型研究，重点研究类固醇受体的表达 和功能。开发一种使用PRM的长期无雌激素避孕方法，也可以防止P 对乳房采取行动可能是一种具有双重好处的避孕方法，即防止怀孕。 和乳房疾病。关于胎膜早破对子宫内膜影响的新发现证明了进一步的临床评估的合理性。目标3： 第一项临床研究将探讨CDB 2914经阴道环产时对子宫内膜的影响。 剂量抑制排卵。子宫内膜组织学和增殖标记物将随着时间的推移而确定。一个 第二项临床研究将评估PRM环使用12周后连续两周的孕激素疗程 会逆转子宫内膜的任何变化。第三项临床研究将评估小剂量CDB的疗效。 2914使用宫内系统仅引起局部效应，而正常排卵 维护好了。目的4：建立人子宫内膜上皮细胞(HEEC)分子模型 孕激素与CDB-2914和SPRM作用的比较研究及表征 子宫内膜：a)在雌激素存在或不存在的情况下，确定细胞周期相关的影响，比较 用几种方法比较孕激素(P4；醋酸甲羟孕酮，MPA)与CDB-2914的活性 永生化人子宫内膜癌细胞；b)比较SPRM、孕激素、雌激素或 顺序激素暴露对HEEC功能的影响，使用基因表达和蛋白质组学分析。项目 III结合基础、翻译和临床研究，进一步确定CDB-2914对人类的安全性 使用以及表征这种PRM的分子机制。