Paracrine Regulation of BPH Pathogenesis

描述（由申请人提供）：良性前列腺增生（BPH）是成年男性人群中前列腺增生的重要原因，也是人类最常见的症状性肿瘤样疾病。临床上，BPH导致尿道收缩，随之而来的是尿流率减慢和不能适当地排空膀胱。在西方世界，BPH不是一种危及生命的疾病。然而，它是一种具有显著相关发病率和随之而来的医疗保健成本的病症。BPH会导致各种问题，包括尿失禁、尿频、尿急和尿后滴漏，更严重的是，它会导致肾功能不全（血清肌酐升高）、频繁的尿路感染和尿脓毒症（由于尿引流不足）。几十年来，对BPH的研究核心一直围绕着雄激素和雌激素信号。这些研究促进了51-还原酶抑制剂如非那雄胺和度他雄胺的开发。然而，这些方向在开发新方法以改善患者状况方面并没有显示出太多的最新进展。迫切需要新的概念来推动该领域的发展。该建议的中心假设是前列腺炎症导致基质改变，导致局灶性良性腺体扩张。这项工作的长期目标是确定可以单独作为化学预防形式或沿着与当前标准BPH治疗共同靶向的途径，以提供安全和长期的症状缓解。该提案解决了最近发布的NIDDK前列腺研究战略计划的一些高优先级建议，包括：创建新模型;了解前列腺中多种细胞类型之间的信号传导，相互作用和串扰;以及表征疾病相关的细胞通路以用于潜在的治疗应用。该提案中的三个具体目标涉及BPH发病机制的相互关联的方面。第一个目的是研究炎症细胞因子表达对前列腺上皮和间质分化的影响。第二个目的是检查这些变化与骨髓来源的细胞群的募集有关的后果以及这些细胞群在增生性生长中的作用。第三个目标是研究核因子-κ B作为影响BPH发病机制的一种策略。 公共卫生相关性：良性前列腺增生（BPH）的根本原因尚不清楚，但可能涉及前列腺炎症。目前的治疗旨在减少雄激素刺激和放松前列腺平滑肌。该项目将研究炎症反应促进良性前列腺肥大的潜力，以期增加治疗选择，以减缓前列腺生长或缓解BPH症状。

DESCRIPTION (provided by applicant): Benign prostatic hyperplasia (BPH) is an important cause of orbidity in the adult male population and is the most common symptomatic tumor-like condition in humans. Clinically BPH results in urethral constriction with a consequent slowing of urinary flow rates and an inability to properly empty the urinary bladder. In the Western world BPH is not a life threatening condition. However, it is a condition with significant associated morbidity and consequent healthcare costs. BPH results in a variety of problems including nocturia, frequency, urgency and post-mictural dribbling and, more seriously it can cause renal insufficiency (with rising serum creatinine), frequent urinary tract infections and urosepsis due to insufficient urinary draining. For many decades the core of research into BPH has centered around androgen and estrogen signaling. These studies have given rise to the development of 51-reductase inhibitors such as finasteride and dutasteride. However these directions have not shown much recent progress in developing new approaches to improve the situation of patients. New concepts are sorely needed to move the field forwards. The central hypothesis of this proposal is that prostatic inflammation results in a profile of stromal changes which contribute to focal benign glandular expansion. The long term goal of this work is to identify pathways which can be co-targeted ether alone as a form of chemoprevention or along with current standard BPH therapies to provide safe and long term symptomatic relief. This proposal addresses a number of the high priority recommendations of the recently published NIDDK Prostate Research Strategic Plan including; the creation of new models; the development of an understanding of the signaling, interaction and crosstalk between multiple cell types in the prostate; and, the characterization of disease-relevant cellular pathways for potential therapeutic applications. The three specific aims in this proposal address interlocking aspects of BPH pathogenesis. The first aim looks at the effects of inflammatory cytokine expression on prostatic epithelial and stromal differentiation. The second aim examines the consequences of these changes in relation to the recruitment of bone marrow- derived cell populations and the contribution that these play in hyperplastic growth. The third aim examines the targeting of nuclear factor-kappa B as a strategy to influence BPH pathogenesis. PUBLIC HEALTH RELEVANCE: The root causes of benign prostatic hyperplasia (BPH) are unclear ut likely involve inflammation in the prostate. Current treatments aim to reduce androgenic stimulation and to relax prostatic smooth muscle. This project will investigate the potential of inflammatory responses to contribute to benign prostatic enlargement with a view to adding treatment options to either slow prostatic growth or relieve symptoms of BPH.