Estrogen receptors in benign prostatic hyperplasia

描述（由申请人提供）：BPH引起的恼人的下尿路症状（LUTS）很常见，在老年男性中发病率很高。F30奖学金项目的长期目标是提高对雌激素受体（ER）在BPH中的作用的理解，并开发新的治疗策略来对抗这种常见疾病的过程。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的重要优先事项，为未来攻读医学博士学位的内科科学家的培训和职业发展提供帮助。BPH的病因一直被认为是由性类固醇激素诱导的发育的病理再现，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，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的雄性狗会导致更早发作和更广泛的BPH，而用T+E2治疗的雄性大鼠会出现前列腺肥大和排尿障碍。初步研究表明，在模拟老年男性激素环境的生理浓度下，用T+E2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通过遗传策略确定雌激素受体在前列腺中介导这些作用的重要作用：

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.