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。排尿症状发生在许多情况下，由于膀胱出口梗阻（BOO）。虽然BOO的根本原因尚不清楚，可能是多因素的，但BOO通常与良性前列腺增生（BPH）有关，这是老年男性中另一种高度流行的疾病。虽然BPH和BOO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：老年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。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，以模拟老年人男性中激素环境的剂量用睾酮+雌二醇（T+E2）处理的雄性小鼠发展了前列腺的良性增大，这与沿着尿道出现类似于发育的前列腺芽的增殖灶有关，前列腺前尿道区域的形态学改变，以及提示BOO的尿潴留的高发生率。引人注目的是，与2个月大的小鼠相比，18个月大的小鼠中膀胱诱发的尿潴留的严重程度高出4倍以上，表明该模型重现了在人类中也观察到的对BOO的年龄依赖性易感性。前列腺素诱导的小鼠模型也表现出前列腺中的基因表达变化，据报道，这种变化发生在与BOO相关的人类BPH中，包括分泌型卷曲相关蛋白1（Sfrp 1）的上调。使用几种方法，包括创建和研究Sfrp 1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，Sfrp 1信号通过非经典的WNT/JNK通路作为前列腺发育过程中的促增殖信号，可以被增选引发成人前列腺的异常增殖。这些数据表明Sfrp 1可能是BPH病理学的介导者，而不仅仅是BPH的生物标志物。我们推测与BOO相关的BPH亚型是由包括SFRP 1/JNK信号传导在内的发育生长调节途径的重新激活引起的。这一假设将使用多学科方法进行测试，其中包括对小鼠模型的评估以及与外科病理学家Wei Huang M.D.的合作，他们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信号传导。 公共卫生相关性：良性前列腺增生（BPH）和膀胱出口梗阻是老年男性的常见问题，经常一起发生，需要从药物治疗到手术的医疗干预。目前治疗的局限性导致需要为患有BPH和膀胱出口梗阻的男性提供额外的治疗选择。该项目通过进行机制研究来解决额外治疗选择的需求，这些机制研究将确定推动BPH和膀胱出口梗阻发展的新分子途径。预计这些分子通路将成为未来BPH和膀胱出口梗阻临床治疗的靶点。

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. PUBLIC HEALTH RELEVANCE: Benign prostatic hyperplasia (BPH) and bladder outlet obstruction are common problems in aging men that often occur together and require medical intervention ranging from drug therapy to surgery. The limitations of current therapies create a need for additional treatment options for men suffering from BPH and bladder outlet obstruction. This project addresses the need for additional treatment options by conducting mechanistic studies that will identify new molecular pathways that drive the development of BPH and bladder outlet obstruction. It is anticipated that these molecular pathways will serve as future therapeutic targets in the clinical management of BPH and bladder outlet obstruction.