Androgen signaling in benign prostatic hyperplasia (BPH)

良性前列腺增生 (BPH) 中的雄激素信号传导

• 批准号: 8528568
• 负责人: JOEL B NELSON
• 金额: $ 30.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528568
• 关键词: 5a-Reductase Inhibition; Affect; Age; Aging; Androgen Receptor; Androgens; Anti-Inflammatory Agents; Anti-inflammatory; Benign Prostatic Hypertrophy; Blinded; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Code; Complex; Coupled; Development; Disease; Drug Exposure; Epithelial; Finasteride; Functional disorder; Gene Expression; Genes; Human; Hyperplasia; Immunohistochemistry; Inflammation; Knowledge; Lead; Ligands; Literature; Mediating; Molecular; Nature; Nodule; Non-Steroidal Anti-Inflammatory Agents; Normal Cell; Operative Surgical Procedures; Oxidoreductase; Pathogenesis; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Prevention; Prostate; Prostatectomy; Radical Prostatectomy; Randomized; Receptor Activation; Recruitment Activity; Relative (related person); Research; Research Personnel; Research Project Grants; Resected; Role; Schedule; Services; Signal Pathway; Signal Transduction; Specimen; Testing; Testosterone; Time; Tissue Banks; Tissues; Transcript; Universities; Urology; age effect; aged; arm; base; blind; celecoxib; clinical practice; clinically significant; indexing; inhibitor/antagonist; insight; laser capture microdissection; lower urinary tract symptoms; men; novel strategies; prostate transurethral resection; public health relevance; research study; response; transcription factor; translational study

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.

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) 的征兆。雄激素和衰老是 BPH 发病机制中两个已知的重要因素。此外，炎症等其他因素也与良性前列腺增生的发生有关。雄激素反应性的偏差被认为是 BPH 发生的关键步骤。然而，这种偏差的分子性质仍不清楚。最近，我们研究了人类 BPH 标本中 4 种雄激素反应基因的表达，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 中相对于邻近正常细胞增加了约 4 倍。我们的目标是探索导致 BPH 雄激素信号升高的机制。假设衰老、炎症和/或 5a-还原酶 II 活性增加可以增强 BPH 中的雄激素信号传导。提出了两个具体目标来检验上述假设。 1. 确定 BPH 和衰老人类前列腺中雄激素信号的变化。可提供 BPH 标本和供体前列腺组织。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反应基因的表达来评估雄激素信号传导。 2. 进行 II 期临床试验，以检验以下假设：塞来考昔（一种非类固醇抗炎药 (NSAID)）和/或非那雄胺（一种 5a-还原酶 II 抑制剂）可以抑制雄激素反应基因的升高表达患者的 BPH 组织。一项四组、II 期随机、单盲临床试验将在患有 BPH 的男性中进行，这些男性对雄激素操作和长期暴露于非甾体抗炎药 (NSAID) 不熟悉。随机分组后，男性将单独或联合使用塞来昔布和非那雄胺研究药物，或不接受任何治疗（并严格避免使用 NSAID 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不知情。该应用中的基础、转化和临床研究将深入了解 BPH 中异常升高的雄激素信号传导，这可能会导致该疾病的新预防和/或治疗。 公共健康相关性：该项目将研究衰老、炎症和 5a-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。

项目成果

Corrigendum to "Physical and Functional Interactions between ELL2 and RB in the Suppression of Prostate Cancer Cell Proliferation, Migration, and Invasion" [Neoplasia 19 (2017) 207-215].

“ELL2 和 RB 在抑制前列腺癌细胞增殖、迁移和侵袭中的物理和功能相互作用”的勘误表 [Neoplasia 19 (2017) 207-215]。

• DOI: 10.1016/j.neo.2017.05.005
• 发表时间: 2017
• 期刊: Neoplasia (New York, N.Y.)
• 作者: Qiu,Xiaonan;Pascal,LauraE;Song,Qiong;Zang,Yachen;Ai,Junkui;O'Malley,KatherineJ;Nelson,JoelB;Wang,Zhou
• 通讯作者: Wang,Zhou