Androgen signaling in benign prostatic hyperplasia (BPH)

描述（由申请人提供）：BPH中的雄激素信号传导：下尿路症状（LUTS）影响约30%的50岁及以上男性，通常被认为是具有临床意义的良性前列腺增生（BPH）的体征。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，也涉及BPH的发展。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个雄激素反应基因在人BPH标本中的表达，发现反映多个雄激素反应基因表达的复合雄激素反应指数在BPH中相对于邻近的正常细胞增加约4倍。我们的目的是探讨导致BPH雄激素信号升高的机制。假设是衰老、炎症和/或5 α-还原酶II活性增加可以增强BPH中的雄激素信号传导。提出了两个具体目标来检验上述假设。1.确定BPH和老化人类前列腺中雄激素信号的改变。BPH标本和供体前列腺组织可用。将通过激光捕获显微切割（LCM）结合实时PCR和免疫组织化学测定雄激素应答基因的表达来评估雄激素信号传导。2.进行II期临床试验，以检验塞来昔布（一种非甾体抗炎药（NSAID））和/或非那肽（一种5 α-还原酶II抑制剂）可抑制患者BPH组织中雄激素应答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，这些患者不接受雄激素操作和长期NSAID暴露。随机化后，男性将暴露于研究药物塞来昔布和非那肽单独或联合或不治疗（严格避免NSAID和5 α-还原酶抑制剂）4周。将对采集的所有标本进行编码，并对进行分子和组织学分析的研究者设盲。本申请中的基础、转化和临床研究将为BPH中异常升高的雄激素信号传导提供见解，这可能导致该疾病的新预防和/或治疗。 公共卫生相关性：该项目将研究衰老，炎症和5 α-还原酶II在良性前列腺增生（BPH）雄激素反应基因表达升高中的作用。阐明BPH中雄激素信号异常升高的机制可能会导致BPH预防和/或治疗的新方法。

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.