Steroid hormones and SFRP1 in the age-related incidence of BPH and BOO

描述（由申请人提供）：下尿路症状（LUTS），包括膀胱排尿症状，是老年男性的常见问题。由于膀胱出口梗阻（BOO），许多病例出现排尿症状。虽然BOO的潜在原因尚不清楚，可能是多因素的，但BOO通常与良性前列腺增生（BPH）有关，BPH是老年男性中另一种非常普遍的疾病。虽然BPH和BOO的病因尚不清楚，但现有数据与衰老男性激素水平的变化和/或发育生长调节途径的重新激活是BPH和相关BOO的潜在原因的假设是一致的。为了支持类固醇激素在BPH和BOO中的潜在作用，我们的初步研究表明，用睾酮+雌二醇（T+E2）治疗的雄性小鼠，其剂量模仿衰老男性的激素环境，出现前列腺良性肿大，并伴有沿尿道增生灶的外观，类似于发育中的前列腺芽，前列腺尿道周围区域的形态改变。尿潴留的高发生率表明有BOO。引人注目的是，与2个月大的小鼠相比，18个月大的小鼠激素引起的尿潴留的严重程度要高出4倍以上，这表明该模型概括了人类对BOO的年龄依赖性易感性。激素诱导的小鼠模型也显示出前列腺基因表达的变化，这些变化已被报道发生在与BOO相关的人类BPH中，包括分泌卷曲相关蛋白1 （strp1）的上调。通过多种方法，包括创建和研究strp1基因敲除和转基因小鼠以及体外实验，我们发表的和初步的研究表明，通过非规范的WNT/JNK途径，strp1信号作为前列腺发育过程中的促增殖信号，可以被用来触发成人前列腺的异常增殖。这些数据表明，strp1可能是BPH病理的介质，而不仅仅是BPH的生物标志物。我们假设与BOO相关的一种BPH亚型是由包括SFRP1/JNK信号在内的发育生长调控通路的重新激活引起的。这一假设将通过多学科的方法进行验证，包括小鼠模型的评估，并与外科病理学家黄炜医学博士合作，他将协助我们评估人类患者样本中的发育生长因子途径和JNK信号。

DESCRIPTION (provided by applicant): Lower urinary tract symptoms (LUTS), including bladder voiding symptoms, are a common problem in aging men. Voiding symptoms occur in many cases due to bladder outlet obstruction (BOO). While the underlying causes of BOO are unclear and may be multi-factorial, BOO is often found in association with benign prostatic hyperplasia (BPH), another highly prevalent condition in aging men. While the etiology of BPH and BOO remain largely unclear, available data are consistent with the hypothesis that changing hormone levels in aging men and/or the reactivation of developmental growth-regulatory pathways are underlying causes of BPH and associated BOO. In support of the potential role of steroid hormones in BPH and BOO, our preliminary studies showed that male mice treated with testosterone + estradiol (T+E2) at doses that mimic the hormonal milieu in aging human males developed benign enlargement of the prostate that was associated with the appearance of proliferating foci along the urethra that resembled developmental prostatic buds, changes in the morphology of the prostatic peri- urethral region, and a high incidence of urinary retention indicative of BOO. Strikingly, the severity of hormone-induced urinary retention was more than 4-fold greater in 18-month-old mice compared to 2-month-old mice indicating that this model recapitulates the age-dependent susceptibility to BOO that is also seen in humans. The hormone-induced mouse model also exhibited gene expression changes in the prostate that have been reported to occur in human BPH associated with BOO, including the up-regulation of Secreted frizzled related protein 1 (Sfrp1). Using several approaches including the creation and study of Sfrp1 knockout and transgenic mice as well as in vitro experiments, our published and preliminary studies have implicated Sfrp1 signaling via the non-canonical WNT/JNK pathway as a pro-proliferative signal during prostatic development that can be co-opted to trigger abnormal proliferation in the adult prostate. These data suggest that Sfrp1 is likely to be a mediator of BPH pathology rather than merely a biomarker for BPH. We hypothesize that a sub-type of BPH associated with BOO is caused by the reactivation of developmental growth-regulatory pathways including SFRP1/JNK signaling. This hypothesis will be tested using a multi-disciplinary approach that will include an evaluation of mouse models and a collaboration with a surgical pathologist, Wei Huang M.D., who will assist us in evaluating developmental growth factor pathways and JNK signaling in human patient samples.