Paracrine Regulation of BPH Pathogenesis

描述(申请人提供)：良性前列腺增生症(BPH)是成年男性人群疾病的重要原因，也是人类最常见的症状性肿瘤样疾病。临床上，良性前列腺增生症会导致尿路狭窄，继而导致尿流率减慢，无法正常排空膀胱。在西方世界，良性前列腺增生症不会危及生命。然而，这是一种与显著相关的发病率和随之而来的医疗费用相关的疾病。BPH会导致各种问题，包括夜尿症、尿频、尿急和尿流，更严重的是，它会导致肾功能不全(血肌酐升高)、频繁的尿路感染和由于尿液引流不足而导致的尿毒症。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。这些研究催生了51-还原酶抑制剂的开发，如非那雄胺和度他雄胺。然而，这些方向在开发改善患者状况的新方法方面并没有显示出太多最近的进展。推动这一领域向前发展迫切需要新的概念。这一建议的中心假设是前列腺炎症导致一系列间质改变，这有助于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使用乙醚作为一种化学预防形式或与当前标准的BPH疗法一起提供安全和长期的症状缓解的共同靶点的途径。这项建议涉及最近发表的NIDDK前列腺研究战略计划中的一些高度优先的建议，包括：创建新的模型；开发对前列腺中多种细胞类型之间的信号、相互作用和串扰的理解；以及表征潜在治疗应用的与疾病相关的细胞路径。这项提案中的三个具体目标涉及BPH发病机制的连锁方面。第一个目的是观察炎性细胞因子表达对前列腺上皮和间质分化的影响。第二个目的是研究这些变化对骨髓源性细胞群体招募的影响，以及这些变化在增生性生长中所起的作用。第三个目的是研究核因子-kappa B作为影响BPH发病机制的一种策略。

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.