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

描述(申请人提供)：下尿路症状(LUT)，包括膀胱排尿症状，是老年男性的常见问题。许多病例出现排尿症状是由于膀胱出口梗阻(BOO)。虽然BOO的潜在原因尚不清楚，可能是多因素的，但BOO经常被发现与良性前列腺增生症(BPH)有关，BPH是老年男性的另一种高度常见的疾病。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/或发育生长调节通路的重新激活是BPH和相关BOO的根本原因。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，用睾酮+雌二醇(T+E2)以模拟老年男性荷尔蒙环境的剂量治疗的雄性小鼠出现良性的前列腺增大，这与沿尿道出现类似发育的前列腺芽的增殖灶、前列腺周围区域的形态变化以及指示BOO的尿潴留的高发生率有关。引人注目的是，18个月大的小鼠由激素引起的尿潴留的严重程度是2个月大的小鼠的4倍以上，这表明这个模型概括了人类也可以看到的与年龄相关的BOO易感性。荷尔蒙诱导的小鼠模型也显示出与人BPH相关的BOO相关的前列腺基因表达变化，包括分泌卷曲相关蛋白1(SFRP1)的上调。利用几种方法，包括建立和研究SFRP1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，SFRP1信号通过非规范的WNT/JNK途径在前列腺发育过程中作为促增殖信号，可以被选为触发成年前列腺异常增殖的信号。这些数据表明，SFRP1可能是BPH病理的中介，而不仅仅是BPH的生物标记物。我们假设，与BOO相关的BPH的一个亚型是由包括SFRP1/JNK信号在内的发育生长调节通路的重新激活引起的。这一假设将使用多学科方法进行验证，其中将包括对小鼠模型的评估，以及与外科病理学家黄伟医学博士的合作，黄伟医生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.