Estrogen Regulation in BPH and the Lower Urinary Tract

描述（由申请人提供）：该项目的长期目标是开发更好的方法来预防和治疗男性下尿路症状（LUTS）。良性前列腺增生（BPH）发生在绝大多数男性中，并导致称为LUTS的发病率。对男性BPH引起的LUTS进行临床治疗是医疗保健的一项重大成本，对生活质量产生不利影响，并导致男性和女性的死亡风险。虽然BPH的病因在很大程度上仍不清楚，但现有数据与以下假设一致：激素水平的变化，特别是睾酮（T）和雌二醇-17 b（E2），是BPH和膀胱出口梗阻（BOO）的潜在原因。为了支持这一观点，前列腺肥大男性的护理标准针对雄激素途径。然而，随着男性年龄的增长，雄激素的数量显着减少，而雌激素与睾酮的比例增加。这表明雌激素可能是BPH和相关BOO的表现或维持的重要途径。来自我们和其他人的新的未发表的数据暗示睾酮代谢物E2是BPH的关键介质。然而，很少有人知道雌激素如何引起它们在前列腺中的作用，并且存在很少的BPH和BOO模型，这将允许对分子途径进行遗传和药理学解剖。在这方面，我们已经开发了一种新的遗传学上易于处理的小鼠模型，其中用T+E2处理的雄性动物模仿老年男性的激素环境，发展出与男性中发现的BPH一致的下泌尿生殖道异常。这些标准包括：新的腺性前列腺生长、前列腺尿道狭窄、进行性膀胱增大以及高频率和低容量的排尿模式。我们的初步数据暗示E2/雌激素受体（ER）信号传导，特别是ER-α/α同源二聚体作为下泌尿生殖道异常的关键分子决定因素，这在BPH男性中一直存在。此外，我们已经观察到在BPH的人类标本和我们的动物模型中成纤维细胞生长因子（FGF）和活化的FGF受体的表达增加。我们假设下泌尿生殖道内的异常是由不适当的E2/ER信号传导介导的，反过来影响旁分泌作用的雌激素，促进BPH和相关BOO。 公共卫生相关性：在衰老过程中，几乎所有的男性都会经历某种形式的下尿路症状（LUTS），通常是由于良性前列腺增生（BPH）。除了发病率和生活质量问题外，LUTS还显著影响男性和女性的死亡风险高达50%。这项研究通过进行雌激素作用机制的研究来解决泌尿外科领域的迫切需要，这些研究支持了BPH相关的分子途径。这些研究的期望是针对目前未知的BPH相关途径开发治疗靶点，从而预防或治疗这种疾病。

DESCRIPTION (provided by applicant): The long term objective of this project is to develop better methods for the prevention and treatment of lower urinary tract symptoms (LUTS) in men. Benign prostatic hyperplasia (BPH) occurs in a vast majority of men and contributes to the morbidity known as LUTS. Clinical treatment for LUTS ascribed to BPH in men is a significant cost in healthcare, adversely affecting quality of life, and contribute to the mortality risk in men and women. While the etiology of BPH remains largely unclear available data are consistent with the hypothesis that changing hormone levels, especially testosterone (T) and estradiol-17b (E2), are underlying causes of BPH and bladder outlet obstruction (BOO). In support of this idea the standard of care for men with enlarged prostates targets the androgenic pathway. However, as men age the amount of androgens significantly decrease while the estrogen to testosterone ratio increases. This posits that estrogens may be an important pathway in the manifestation or maintenance of BPH and associated BOO. New unpublished data from us and others implicates the testosterone metabolite E2 as a key mediator of BPH. However, little is known how estrogens may elicit their affects in the prostate and few models of BPH and BOO exist that will allow for the genetic and pharmacologic dissection of molecular pathways. In this regard, we have developed a new genetically tractable mouse model in which males treated with T+E2, to mimic the hormonal milieu in aging men, develop lower urogenital tract abnormalities consistent with BPH found in men. These criteria include: new glandular prostatic growth, prostatic urethral narrowing, progressively enlarged bladders, and urination patterns of high frequency and low volume. Our preliminary data implicate E2/estrogen receptor (ER)-signaling and specifically ER-a/a homodimerization as a key molecular determinant of lower urogenital tract abnormalities that are consistently found in men with BPH. Furthermore, we have observed increased expression of fibroblast growth factors (FGFs) and activated FGF receptors in human specimens of BPH and in our animal models. We hypothesize that abnormalities within the lower urogenital tract are mediated by inappropriate E2/ER-signaling in turn affecting paracrine acting estromedins to promote BPH and associated BOO. PUBLIC HEALTH RELEVANCE: During the aging process nearly all men experience some form of lower urinary tract symptoms (LUTS), often due to benign prostatic hyperplasia (BPH). In addition to morbidity and quality of life issues, LUTS also significantly affects mortality risk by up to 50% in men and women. The proposed research addresses an urgent need in the urological field by performing estrogen hormone action mechanistic studies that underpin molecular pathways involved in BPH. The expectation of these studies is to develop therapeutic targets towards currently unknown pathways involved in BPH and hence prevent or treat this disease.