Estrogen receptors in benign prostatic hyperplasia

良性前列腺增生中的雌激素受体

• 批准号: 8452516
• 负责人: Tristan Marriner Nicholson
• 金额: $ 4.72万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-14 至 2016-09-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452516
• 关键词: Address; Age; Agonist; Americas; Androgens; Benign; Benign Prostatic Hypertrophy; Biological Models; Bladder; Canis familiaris; Clinical; Data; Dentistry; Development; Disease; Doctor of Philosophy; Ductal; Endocrine; Environment; Epithelial; Estradiol; Estrogen Antagonists; Estrogen Receptors; Estrogen Therapy; Estrogens; Etiology; Evaluation; FDA approved; Faculty; Fellowship; Fulvestrant; Functional disorder; Future; Genetic; Goals; Gonadal Steroid Hormones; Grant; Growth; Health; Hormonal; Hormones; Human; Implant; Increased frequency of micturition; International; Intervention; Knockout Mice; Lead; Lower urinary tract; Mediating; Mediation; Mediator of activation protein; Medical; Mentors; Modeling; Molecular; Morbidity - disease rate; Mus; Nocturia; Nude Mice; Pathologic; Pathway interactions; Patients; Peer Review; Physicians; Physiological; Population; Prevalence; Prevention; Process; Prostate; Prostatic; Prostatic Diseases; Prostatic duct; Prostatic hypertrophy; Publications; Raloxifene; Rattus; Research; Research Project Grants; Research Support; Role; Scientist; Selective Estrogen Receptor Modulators; Serum; Specificity; Students; Syndrome; Techniques; Testing; Testosterone; Therapeutic; Tissues; Training; Training Programs; United States National Institutes of Health; Universities; Urethra; Urinary tract; Urination; Urology; Wisconsin; Work; Writing; Xenograft procedure; career; career development; clinical practice; clinically relevant; combat; disorder prevention; early onset; experience; gain of function; human disease; improved; indexing; loss of function; lower urinary tract symptoms; male; medical schools; meetings; member; men; mouse model; novel therapeutics; older men; pre-clinical; prevent; programs; receptor; receptor function; research study; skills; success

DESCRIPTION (provided by applicant): Bothersome lower urinary tract symptoms (LUTS) due to BPH are common and cause significant morbidity among older men. The long-term objective of this F30 fellowship project is improved understanding of estrogen receptor (ER) action in BPH and development of novel therapeutic strategies to combat this common disease process. The proposed F30 fellowship project addresses important priorities in benign prostate disease research by using a translational mouse model system to study endocrine effects on the male lower urinary tract in the training and career development of a future physician-scientist working toward the MD and PhD degrees. The etiology of BPH has long been attributed to pathologic recapitulation of development induced by sex steroid hormones, but the underlying molecular mechanisms have not been elucidated. As men age, serum testosterone (T) decreases while estradiol (E2) increases, paralleling the development of BPH and LUTS. Treatment of male dogs with androgens and estrogens induces earlier onset and more extensive BPH, and male rats treated with T+E2 develop enlarged prostates and obstructive voiding. Preliminary studies show that male mice treated with T+E2, in physiologic concentrations that mimic the hormonal milieu of older men, develop prostatic ductal growth, urethral narrowing and voiding dysfunction. The proposed fellowship research will determine the estrogen receptor important for mediation of these effects in the prostate with genetic strategies: use of ER knockout mice and tissue-specific ER knockout mice to determine receptor subtype and the importance of stromal versus epithelial ERs in BPH. Pharmacologic strategies to determine the necessity of ER will involve treatment of mice with T and selective ER-agonists and the evaluation of prostate growth, ductal branching and clinical sequelae of BPH. Prevention of BPH development will be tested with experimental selective estrogen receptor modulators (SERMs) that target relevant ER subtypes and the clinically relevant SERMs Raloxifene and Fulvestrant. Raloxifene will also be studied as a potential therapeutic strategy in nude mice implanted with human BPH xenografts. The goal of this fellowship research will be to elucidate the ER underlying induction of these effects in this mouse model and evaluate SERMs as potential therapies for BPH. PUBLIC HEALTH RELEVANCE: For reasons that are still not very well understood, most men in America will develop prostate growth (benign prostatic hyperplasia, or BPH) and trouble with urination as they age. This disease process represents a substantial financial and health burden for our population. Sex steroid hormones, including estrogens, are important contributors to BPH. This research project uses a mouse model to address the mechanism of estrogen receptor action in BPH, tests anti-estrogen therapy for BPH in mouse and human models, and will lead to improved understanding and prevention of this disease.

描述（由申请人提供）：BPH引起的令人烦恼的下尿路症状（LUTS）在老年男性中很常见，并导致显著的发病率。这个F30奖学金项目的长期目标是提高对BPH中雌激素受体（ER）作用的理解，并开发新的治疗策略来对抗这种常见的疾病过程。拟议的F30奖学金项目通过使用翻译小鼠模型系统来研究内分泌对男性下尿路的影响，以解决良性前列腺疾病研究中的重要优先事项，以培养未来的医学科学家，并致力于获得MD和博士学位。BPH的病因一直被认为是性类固醇激素诱导的病理性发育重演，但其潜在的分子机制尚未阐明。随着男性年龄的增长，血清睾酮（T）下降，而雌二醇（E2）增加，与BPH和LUTS的发展平行。用雄激素和雌激素治疗雄性狗可诱导更早发病和更广泛的前列腺增生，用T + E2治疗的雄性大鼠出现前列腺肥大和排尿阻塞。初步研究表明，用T + E2（生理浓度模拟老年男性的激素环境）治疗的雄性小鼠会出现前列腺导管生长、尿道狭窄和排尿功能障碍。拟议的奖学金研究将确定雌激素受体的重要调解这些影响在前列腺与遗传策略： 使用ER敲除小鼠和组织特异性ER敲除小鼠确定受体亚型和BPH中基质ER与上皮ER的重要性。确定ER必要性的药理学策略将涉及用T和选择性ER激动剂治疗小鼠，以及评估前列腺生长、导管分支和BPH的临床后遗症。将使用靶向相关ER亚型的实验性选择性雌激素受体调节剂（SERM）和临床相关SERM雷洛昔芬和氟维司群检测BPH发生的预防作用。雷洛昔芬也将作为一种潜在的治疗策略，在植入人BPH异种移植物的裸鼠中进行研究。这项研究的目标是阐明ER在这种小鼠模型中诱导这些效应的基础，并评估SERM作为BPH的潜在治疗方法。 公共卫生相关性：由于目前还不太清楚的原因，美国大多数男性随着年龄的增长会出现前列腺增生（良性前列腺增生，或BPH）和排尿困难。这一疾病进程给我国人民带来了巨大的财政和健康负担。性类固醇激素，包括雌激素，是BPH的重要贡献者。该研究项目使用小鼠模型来解决BPH中雌激素受体作用的机制，在小鼠和人类模型中测试BPH的抗雌激素治疗，并将提高对这种疾病的理解和预防。