Androgen signaling in benign prostatic hyperplasia (BPH)

描述(申请人提供)：BPH中的雄激素信号：下尿路症状(LUTS)影响约30%50岁及以上的男性，通常被认为是临床上显著的良性前列腺增生症(BPH)的迹象。雄激素和衰老是BPH发病的两个重要因素。此外，其他因素，如炎症，也与BPH的发生有关。雄激素反应性的偏离被认为是BPH启动的关键步骤。然而，这种偏离的分子本质仍不清楚。最近，我们研究了4个雄激素反应基因在人BPH组织中的表达，发现反映多种雄激素反应基因表达的综合雄激素反应指数在BPH组织中较邻近的正常细胞增加了~4倍。我们的目标是探索导致BPH雄激素信号升高的机制。假说是，衰老、炎症和/或5a-还原酶II活性增加可以增强BPH中的雄激素信号。为了检验上述假设，本文提出了两个具体目标。1.探讨雄激素信号在人前列腺增生症和增龄性前列腺癌中的变化。可获得BPH标本和供体前列腺组织。雄激素信号将通过激光捕获显微切割(LCM)结合实时聚合酶链式反应和免疫组织化学检测雄激素反应基因的表达来评估。2.进行II期临床试验，以验证非类固醇抗炎药(NSAID)塞来昔布和/或5a-还原酶II抑制剂非那雄胺可以抑制患者BPH组织中雄激素反应基因表达升高的假设。一项四臂、II期随机单盲临床试验将在BPH患者中进行，这些患者不喜欢雄激素操作和慢性非甾体抗炎药暴露。随机化后，男性将接受研究药物塞来昔布和非那雄胺单独或联合使用或不接受治疗(以及严格避免非类固醇抗炎药和5a还原酶抑制剂)4周。所有收集的标本都将被编码，并对将进行分子和组织分析的调查人员进行盲目处理。这一应用中的基础、翻译和临床研究将为了解BPH中雄激素信号的异常升高提供洞察力，这可能导致对该疾病的新的预防和/或治疗。 公共卫生相关性：该项目将调查衰老、炎症和5a-还原酶II在良性前列腺增生症(BPH)雄激素反应基因表达升高中的作用。阐明BPH雄激素信号异常升高的机制(S)可能为BPH的预防和/或治疗提供新的途径。

DESCRIPTION (provided by applicant): Androgen signaling in BPH: Lower Urinary Tract Symptoms (LUTS) affects about 30% of men aged 50 and over and is generally considered a sign of clinically significant benign prostatic hyperplasia (BPH). Androgens and aging are two known important factors in BPH pathogenesis. In addition, other factors, such as inflammation, are also implicated in BPH development. Deviation of androgen responsiveness is thought to be a key step in BPH initiation. However, the molecular nature of such a deviation remains unclear. Recently we investigated the expression of 4 androgen-responsive genes in human BPH specimens and found that the composite androgen-response index, which reflects the expression of multiple androgen-responsive genes, is increased ~4-fold in BPH relative to the adjacent normal cells. Our objective is to explore mechanisms leading to the elevated androgen signaling in BPH. The hypothesis is that aging, inflammation, and/or increased 5a- reductase II activity can enhance androgen signaling in BPH. Two specific aims are proposed to test the above hypothesis. 1. Determine the alterations of androgen signaling in BPH and aging human prostate. BPH specimens and donor prostate tissues are available. The androgen signaling will be assessed by determining the expression of androgen-responsive genes by laser capture microdissection (LCM) coupled with real-time PCR and immunohistochemistry. 2. Conduct a Phase II Clinical Trial to test the hypothesis that celecoxib, a non-steroid anti- inflammatory drug (NSAID), and/or finasteride, a 5a-reductase II inhibitor, can inhibit the elevated expression of androgen-responsive genes in BPH tissues in patients. A four-arm, phase II randomized, single-blind clinical trial will be conducted in men with BPH, who are naove to androgen manipulation and chronic NSAID exposure. After randomization, men will be exposed to the study drugs celecoxib and finasteride alone or in combination or to no treatment (and strict avoidance of NSAIDs and 5a-reductase inhibitors) for 4 weeks. All of the specimens collected will be coded and blinded to investigators who will perform molecular and histological analysis. The basic, translational and clinical studies in this application will provide insights into the abnormally elevated androgen signaling in BPH, which may lead to new prevention and/or treatment of the disease. PUBLIC HEALTH RELEVANCE: The project will investigate the roles of aging, inflammation, and 5a-reductase II in elevated expression of androgen-responsive genes in benign prostatic hyperplasia (BPH). Elucidating the mechanism(s) of abnormal androgen signaling elevation in BPH may lead to new approaches for BPH prevention and/or treatment.