Estrogen receptors in benign prostatic hyperplasia

良性前列腺增生中的雌激素受体

• 批准号: 8548104
• 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/8548104
• 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.

描述(由申请人提供)：由于前列腺增生症引起的麻烦的下尿路症状(LUT)很常见，并在老年男性中引起显著的发病率。这个F30奖学金项目的长期目标是提高对雌激素受体(ER)在BPH中作用的了解，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奖学金项目解决了良性前列腺疾病研究中的重要优先事项，通过使用翻译小鼠模型系统来研究在未来攻读医学和博士学位的内科科学家的培训和职业发展中对男性下尿路的内分泌影响。长期以来，BPH的病因一直被认为是性类固醇激素引起的发育的病理重演，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)降低，雌二醇(E_2)升高，与BPH和LUTS的发生发展相平行。用雄激素和雌激素治疗雄犬会导致更早的发病和更广泛的BPH，而用T+E2治疗的雄性大鼠会出现前列腺肥大和排尿梗阻。初步研究表明，在模拟老年男性荷尔蒙环境的生理浓度下，接受T+E2治疗的雄性小鼠会出现前列腺管生长、尿路狭窄和排尿功能障碍。这项拟议的联谊会研究将确定雌激素受体对于通过遗传策略调节前列腺中的这些影响非常重要： 使用ER基因敲除小鼠和组织特异性ER基因敲除小鼠来确定受体亚型以及间质和上皮性ER在BPH中的重要性。确定ER必要性的药理学策略将包括用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。针对相关ER亚型的实验性选择性雌激素受体调节剂(SERM)以及临床上相关的SERM雷洛昔芬和富尔维斯特将用于预防BPH的发展。雷洛昔芬也将作为一种潜在的治疗策略在裸鼠身上进行研究，这些裸鼠被植入了人BPH异种移植瘤。这项联谊会研究的目的将是阐明在这个小鼠模型中诱导这些效应的内质网潜在机制，并评估SERM作为治疗BPH的潜在疗法。