Androgen signaling in benign prostatic hyperplasia (BPH)

描述（由申请人提供）：BPH中的雄激素信号：下尿路症状（LUTS）影响约30%的50岁及以上男性，通常被认为是临床显著的良性前列腺增生（BPH）的征兆。雄激素和衰老是已知的BPH发病的两个重要因素。此外，其他因素，如炎症，也与BPH的发展有关。雄激素反应性的偏离被认为是BPH发生的关键步骤。然而，这种偏离的分子性质仍然不清楚。最近我们研究了4种雄激素应答基因在人前列腺增生标本中的表达情况，发现反映多种雄激素应答基因表达的复合雄激素应答指数在前列腺增生中相对于邻近正常细胞增加了4倍左右。我们的目的是探索前列腺增生中雄激素信号升高的机制。假设是衰老、炎症和/或增加的5a-还原酶II活性可以增强前列腺增生的雄激素信号。本文提出了两个具体目的来检验上述假设。1. 确定前列腺增生和衰老过程中雄激素信号的改变。BPH标本和供体前列腺组织是可用的。雄激素信号将通过激光捕获显微解剖（LCM）结合实时PCR和免疫组织化学检测雄激素应答基因的表达来评估。2. 开展II期临床试验，验证非甾体抗炎药塞来昔布（NSAID）和/或5a-还原酶II抑制剂非那雄胺（finasteride）可以抑制BPH患者组织中雄激素反应基因的升高表达的假设。一项四组、II期随机、单盲临床试验将在男性前列腺增生症患者中进行，这些患者对雄激素操作和慢性非甾体抗炎药暴露缺乏经验。随机分组后，男性将暴露于研究药物塞来昔布和非那雄胺单独或联合或不治疗（严格避免非甾体抗炎药和5a-还原酶抑制剂）4周。所有收集到的标本都将被编码，并对进行分子和组织学分析的研究人员进行盲检。本应用程序的基础、转化和临床研究将为BPH中异常升高的雄激素信号提供见解，这可能导致新的预防和/或治疗疾病。

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.